3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives

ABSTRACT

The invention relates to 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and their use in medicine, particularly in the treatment of pain.

The invention relates to3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decanederivatives, their preparation and use in medicine, particularly invarious neurological disorders, including but not limited to pain,neurodegenerative disorders, neuroinflammatory disorders,neuropsychiatric disorders, substance abuse/dependence.

Opioid receptors are a group of Gi/o protein-coupled receptors which arewidely distributed in the human body. The opioid receptors are currentlysubdivided into four major classes, i.e. the three classical opioidreceptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, anddelta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1)receptor, which was more recently discovered based on its high homologywith said classical opioid receptors. After identification of theendogenous ligand of the ORL-1 receptor, known as nociceptin/orphaninFQ, a highly basic 17 amino acid peptide isolated from tissue extractsin 1995, the ORL-1 receptor was renamed “nociceptin opioid peptidereceptor” and abbreviated as “NOP-receptor”.

The classical opioid receptors (MOP, KOP and DOP) as well as the NOPreceptor are widely distributed/expressed in the human body, includingin the brain, the spinal cord, on peripheral sensory neurons and theintestinal tract, wherein the distribution pattern differs between thedifferent receptor classes.

Nociceptin acts at the molecular and cellular level in very much thesame way as opioids. However, its pharmacological effects sometimesdiffer from, and even oppose those of opioids. NOP-receptor activationtranslates into a complex pharmacology of pain modulation, which,depending on route of administration, pain model and species involved,leads to either pronociceptive or antinociceptive activity. Furthermore,the NOP receptor system is upregulated under conditions of chronic pain.Systemic administration of selective NOP receptor agonists was found toexert a potent and efficacious analgesia in non-human primate models ofacute and inflammatory pain in the absence of side effects. Theactivation of NOP receptors has been demonstrated to be devoid ofreinforcing effects but to inhibit opioid-mediated reward in rodents andnon-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171(16): 3777-3800, and references therein).

Besides the involvement of the NOP receptor in nociception, results frompreclinical experiments suggest that NOP receptor agonists might beuseful inter alia in the treatment of neuropsychiatric disorders (Witkinet al. Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al.,Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858). Remarkably, the DOPreceptor is also implicated to modulate not only pain but alsoneuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).

Strong opioids acting at the MOP receptor site are widely used to treatmoderate to severe acute and chronic pain. However, the therapeuticwindow of strong opioids is limited by severe side effects such asnausea and vomiting, constipation, dizziness, somnolence, respiratorydepression, physical dependence and abuse. Furthermore, it is known thatMOP receptor agonists show only reduced effectiveness under conditionsof chronic and neuropathic pain.

It is known that some of the above mentioned side-effects of strongopioids are mediated by activation of classic opioid-receptors withinthe central nervous system. Furthermore, peripheral opioid receptors,when activated, can inhibit transmission of nociceptive signals shown inboth, clinical and animal studies (Gupta et al., 2001; Kalso et al.,2002; Stein et al., 2003; Zollner et al., 2008).

Thus, to avoid CNS-mediated adverse effects after systemicadministration, one approach has been to provide peripherally restrictedopioid receptor ligands that do not easily cross the blood-brain barrierand therefore distribute poorly to the central nervous system (see forinstance WO 2015/192039). Such peripherally acting compounds mightcombine effective analgesia with limited side-effects.

Another approach has been to provide compounds which interact with boththe NOP receptor and the MOP receptor. Such compounds have for instancebeen described in WO 2004/043967, WO 2012/013343 and WO 2009/118168.

A further approach has been to provide multi-opioid receptor analgesicsthat modulate more than one of the opioid receptor subtypes to provideadditive or synergistic analgesia and/or reduced side effects like abuseliability or tolerance.

On the one hard, it would be desirable to provide analgesics thatselectively act on the NOP receptor system but less pronounced on theclassic opioid receptor system, especially MOP receptor system, whereasit would be desirable to distinguish between central nervous activityand peripheral nervous activity. On the other hand, it would bedesirable to provide analgesics that act on the NOP receptor system andalso to a balanced degree on the MOP receptor system, whereas it wouldbe desirable to distinguish between central nervous activity andperipheral nervous activity.

There is a need for medicaments which are effective in the treatment ofpain and which have advantages compared to the compounds of the priorart. Where possible, such medicaments should contain such a small doseof active ingredient that satisfactory pain therapy can be ensuredwithout the occurrence of intolerable treatment-emergent adverse events.

It is an object of the invention to provide pharmacologically activecompounds, preferably analgesics that have advantages compared to theprior art.

This object has been achieved by the subject-matter of the patentclaims.

A first aspect of the invention relates to3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivativesaccording to general formula (I)

whereinR¹ and R² independently of one another mean

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted; ora 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted;orR¹ and R² together with the nitrogen atom to which they are attachedform a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(A)(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linear orbranched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I:preferably with the proviso that R¹ and R² do not simultaneously mean—H;R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted;R⁴ means

—H:

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(O)₂—;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected throughC₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 6-14-memberedaryl moiety is optionally connected through —C(═O)—, —C(═O)O—,—C(═O)O—CH₂—, or —S(═O)₂—; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;R⁵ meansa 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; ora 5-1 4-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted;R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independently ofone another mean —H, —F, —Cl, —Br, —I, —OH, or —C₁-C₆-alkyl, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;wherein “mono- or polysubstituted” means that one or more hydrogen atomsare replaced by a substituent independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —R²¹, —C(═O)R²¹,—C(═O)OR²¹, —C(═O)NR²¹R²², —C(═O)NH—(CH₂CH₂—O)₁₋₃₀—CH₃,—O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, ═O, —OR²¹, —OC(═O)R²¹,—OC(═O)OR²¹, —OC(═O)NR²¹R²², —NO₂, —NR²¹R²², —NR²¹—(CH₂)₁₋₆—C(═O)R²²,—NR²¹—(CH₂)₁₋₆—C(═O)OR²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²¹C(═O)R²²,—NR²¹C(═O)—OR², —NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —SR²¹, —S(═O)R²¹,—S(═O)₂R²¹, —S(═O)₂OR²¹, and —S(═O)₂NR²¹R²²;whereinR²¹, R²² and R²³ independently of one another mean

—H;

—C₁—C-alkyl, linear or branched, saturated or unsaturated, unsubstitutedor substituted with one, two, three or four substituents independentlyof one another selected from the group consisting of —F, —Cl, —Br, —I,—CN, —OH, —NH₂, —CO₂H, —C(═O)O—C₁-C₆-alkyl, —C(═O)NH₂,—C(═O)NHC₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂, —O—C₁-C₆- alkyl and—S(═O)₂—C₁-C₆-alkyl;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₅-alkyl and —O—C₁-C₆-alkyl;a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²², —NR²¹R²²,—NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², or —S(═O)₂NR²¹R²²,together with the nitrogen atom to which they are attached form a ringand mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; —(CH₂)—S(═O)₂—(CH₂)₂— or—(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H, —C₁-C₆-alkyl,—C(═O)—C₁-C₆-alkyl, or —S(═O)₂—C₁-C₆-alkyl, wherein said —C₁-C₆-alkyl islinear or branched, saturated or unsaturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —OH,—CO₂H, —C(═O)O—C₁-C₆-alkyl and —C(═O)NH₂; and wherein said ring isunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl;or a physiologically acceptable salt thereof.

“(Hetero-)aryl” means “heteroaryl or aryl”. Preferably, aryl includesbut is not limited to phenyl and naphthyl. Preferably, heteroarylincludes but is not limited to -1,2-benzodioxole, -pyrazinyl,-pyridazinyl, -pyridinyl, -primidinyl, -thienyl, -imidazolyl,-benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl,-oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl,-quinazolinyl, -indolyl, -indolinyl, -benzo[c][1.2.5]oxadiazolyl,-imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl. Preferably,cycloalkyl includes but is not limited to -cyclopropyl, -cyclobutyl,-cyclopentyl and -cyclohexyl. Preferably, heterocycloalkyl includes butis not limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl,-piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl, -oxetanyl,-tetrahydropyranyl, and -pyranyl.

When a moiety is connected through an asymmetric group such as —C(═O)O—or —C(═O)O—CH₂—, said asymmetric group may be arranged in eitherdirection. For example, when R⁴ is connected to the core structurethrough —C(═O)O—, the arrangement may be either R⁴—C(═O)O-core orcore-C(═O)O—R⁴.

In preferred embodiments of the compound according to the invention.R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷. R¹⁸, R¹⁹, and R²⁰ independently ofone another mean —H, —F, —OH, or —C₁-C₆-alkyl; preferably —H.

In a preferred embodiment of the compound according to the invention, R¹means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R¹means —H and R² means —CH₃.

In another preferred embodiment of the compound according to theinvention, R¹ means —CH₁; and R² means —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted.Preferably, R¹ means —CH₃ and R² means —CH₃.

In still another preferred embodiment of the compound according to theinvention, R¹ and R² together with the nitrogen atom to which they areattached form a ring and mean —(CH₂)₃₋₆—. Preferably. R¹ and R² togetherwith the nitrogen atom to which they are attached form a ring and mean—(CH₂)₃—.

In yet another preferred embodiment.

-   -   R¹ means —H or —CH₃; and    -   R² means a 3-12-membered cycloalkyl moiety, saturated or        unsaturated, unsubstituted; wherein said 3-12-membered        cycloalkyl moiety is connected through —CH₂—, unsubstituted;        preferably —CH₂-cycloalkyl, —CH₂-cyclobutyl or —CH₂-cyclopentyl;        or R² means a 3-12-membered heterocycloalkyl moiety, saturated        or unsaturated, unsubstituted; wherein said 3-12-membered        heterocycloalkyl moiety is connected through —CH₂—,        unsubstituted; preferably —CH₂-oxetanyl or        —CH₂-tetrahydrofuranyl.

In a preferred embodiment of the compound according to the invention, R³means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with —OCH₃.

In another preferred embodiment of the compound according to theinvention. R³ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted, optionally connected through —C₁-C₆-alkylene-, linearor branched, saturated or unsaturated, unsubstituted. In a preferredembodiment, R³ means -phenyl unsubstituted, mono- or polysubstituted.More preferably, R³ means -phenyl unsubstituted, mono- or disubstitutedwith —F, —Cl, —CH₃, —CF₃, —OH, —OCH₁, —OCF₃ or —OCH₂OCH₃, preferably —F.In another preferred embodiment, R³ means -benzyl unsubstituted, mono-or polysubstituted. More preferably. R³ means -benzyl unsubstituted,mono- or disubstituted with —F, —Cl, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or—OCH₂OCH₃, preferably —F.

In still another preferred embodiment of the compound according to theinvention, R³ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted. Preferably. R³ means -thienyl or -pyridinyl,in each case unsubstituted, mono- or polysubstituted. More preferably,R³ means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in eachcase unsubstituted or monosubstituted with —F, —Cl or —CH₃.

In a preferred embodiment of the compound according to the invention, R⁴means —H.

In another preferred embodiment of the compound according to theinvention, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with a substituent selected from thegroup consisting of —F, —Cl, —Br, —I, —CN, —CF₃, —OH, —O—C₁-C₄-alkyl,—OCF₃, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —OC(═O)C₁-C₄-alkyl,—C(═O)C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁-C₄-alkyl, —C(═O)NHC₁-C₄-alkylene-CN,—C(═O)NHC₁-C₄-alkylene-O—C₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂;—S(═O)C₁-C₄-alkyl, and —S(═O)₂C₁-C₄-alkyl; or with —C(═O)NR²¹R²² whereinR²¹ and R²² together with the nitrogen atom to which they are attachedform a ring and mean —(CH₂)₃₋₆—, —(CH₂)₂—O—(CH₂)₂—, or—(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl; or with—C(═O)NH-3-12-membered cycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH; orwith —C(═O)NH-3-12-membered heterocycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH.More preferably, R⁴ means —C₁-C₆-alkyl, linear or branched saturated orunsaturated, unsubstituted or monosubstituted with —O—C₁-C₄-alkyl or—C(═O)N(C₁-C₄-alkyl)₂.

In still another preferred embodiment of the compound according to theinvention, R¹ means a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein the3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R¹ means a 3-12-membered cycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;wherein said 3-12-membered cycloalkyl moiety is connected through —CH₂—or —CH₂CH₂—. More preferably. R¹ means a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl,—O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered cycloalkyl moiety isconnected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention. R⁴means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably. R⁴ means a 3-12-membered heterocycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered heterocycloalkyl moiety isconnected through —CH₂— or —CH₂CH₂—. More preferably, R¹ means oxetanyl,-tetrahydrofuranyl or -tetrahydropyranyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, —C₁-C₄-alkyl. —O—C₁-C₆-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁₋C₄-alkyl)₂, —S(═O)C₁-C₄-alkyland —S(═O)₂C₁-C₄-alkyl; wherein said -oxetanyl, -tetrahydrofuranyl or-tetrahydropyranyl is connected through —CH₂— or —CH₂CH₂—.

In yet another preferred embodiment of the compound according to theinvention. R⁴ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 6-14-membered aryl moiety is connectedthrough —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably. R⁴ means -phenyl,unsubstituted, mono- or polysubstituted; wherein said -phenyl isconnected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -phenyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid -phenyl is connected through —CH₂— or —CH₂CH₂—.

In a further preferred embodiment of the compound according to theinvention. R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted, wherein said 5-14-membered heteroaryl moietyis connected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said -phenyl is connected through —CH₂— or—CH₂CH₂—. More preferably, R⁴ means -pyridinyl, -pyrimidinyl,-pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,—C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said -pyridinyl, -pyrimidinyl, -pyrazinyl,or -pyrazolinyl is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁵means -phenyl, unsubstituted, mono- or polysubstituted. Preferably, R⁵means -phenyl unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F; —Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃;-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,mono- or polysubstituted; preferably -cyclopropyl, saturated,unsubstituted; -3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted, preferably-pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl,-thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated,unsubstituted or monosubstituted with —C₁-C₄-alkyl; -6-14-membered aryl,unsubstituted, mono- or polysubstituted; preferably -phenyl,unsubstituted; —O—C₁-C₄-alkyl; —S—C₁-C₄-alkyl; —C(═O)OH;—C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH);—C(═O)NH—(CH₂)₁₋₃-3-12-membered cycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —OH; preferably—C(═O)NH—(CH₂)₁₋₃-cyclobutyl, saturated or unsaturated, unsubstituted ormonosubstituted with —OH; —C(═O)-3-12-membered heterocycloalkyl,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably —C(═O)-morpholinyl, saturated, unsubstituted;—S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂.

In another preferred embodiment of the compound according to theinvention, R⁵ means -1,2-benzodioxole, -pyrazinyl, -pyridazinyl,-pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl,-thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl,-benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl,-indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl,-imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl in each caseunsubstituted, mono- or polysubstituted; preferably -pyrazinyl,-pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, in each caseunsubstituted, mono- or polysubstituted. Preferably, R⁵ means-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, in eachcase unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F; —Cl; —Br, —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃;-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,mono- or polysubstituted; preferably -cyclopropyl, saturated,unsubstituted; -3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferably-pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl,-thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated,unsubstituted or monosubstituted with —C₁-C₄-alkyl; -6-14-membered aryl,unsubstituted, mono- or polysubstituted; preferably -phenyl,unsubstituted; —O—C₁-C₄-alkyl; —S—C₁-C₄-alkyl; —C(═O)OH;—C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH);—C(═O)NH—(CH₂)₁₋₃-12-membered cycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —OH; preferably—C(═O)NH—(CH₂)₁₋₃-cyclobutyl, saturated or unsaturated, unsubstituted ormonosubstituted with —OH; —C(═O)-3-12-membered heterocycloalkyl,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably —C(═O)-morpholinyl, saturated, unsubstituted;—S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂.

In still another preferred embodiment of the compound according to theinvention, R⁵ means a bicyclic 9-10-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted. Preferably, R⁵ meansimidazo[1,2-a]pyrazine, unsubstituted or monosubstituted with—C₁-C₄-alkyl.

Preferably, R¹ means -phenyl, -1,2-benzodioxole, -pyrazinyl,-pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl,-benzimidazolyl, -thiazolyl -1,3,4-thiadiazolyl, -benzothiazolyl,-oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl,-quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl,-imidazol[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of

—F; —Cl; —Br, —I;

—CN; —C₁-C₄-alkyl; —CF; —C₁-C₄-alkyl-C(═O)NH₂;—C₁-C₄-alkyl-S(═O)₂—C₁-C₄-alkyl;—C(═O)—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂;—C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —C(═O)NH(C₁-C₄-alkyl-OH);—C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃;—NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH;—NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂;—NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl;—NCH₃C(═O)—C₁-C₄-alkyl;—OH; —O—C₁-C₄-alkyl; —OCF₃; —O—C₁-C₄-alkyl-CO₂H;—O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; —O—C₁-C₄- alkyl-CONH₂;—S—C₁-C₄-alkyl; —S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and—S(═O)₂N(C₁-C₄-alkyl)₂;-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,mono- or polysubstituted; wherein said 3-12-membered cycloalkyl isoptionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—,—NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,—C(═O)NCH₃—(CH₂)₁₋₃—;-3-12-membered heterocycloalkyl, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—,—NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—,—C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—;-6-14-membered aryl, unsubstituted, mono- or polysubstituted; whereinsaid 6-14-membered aryl is optionally connected through —CH₂—, —NH—,—NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—,—C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or-5-14-membered heteroaryl, unsubstituted, mono- or poly substituted;wherein said 5-14-membered heteroaryl is optionally connected through—CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—,—NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—.

In preferred embodiments, the compound according to the invention has astructure according to any of general formulas (II-A) to (VIII-C):

wherein in each caseR¹, R², R³, R⁴, and R⁵ are defined as above,R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; preferably —H or —OH;R^(D) means —H, or —F;or a physiologically acceptable salt thereof.

Preferably, in the compounds according to general formula (I) or any ofthe compounds according to general formulas (II-A) to (VIII-C). R⁵ isselected from the group consisting of:

In a particularly preferred embodiment of the compound according to theinvention

R¹ means —H or —CH₃:R² means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted;cyclopropyl connected through —CH₂—; or tetrahydropyranyl connectedthrough —CH₂—;R³ means -phenyl, benzyl, -thienyl or -pyridinyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —CN, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃,—C(═O)NH₂, C(═O)NHCH₃—C(═O)N(CH₁)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃,—CH₂OH, SOCH₃ and SO₂CH₁; orR⁴ means

—H:

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, —O—C₁-C₄-alkyl, —C(═O)NH—C₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂ or—C(═O)NRR′ wherein R and R′ together with the nitrogen atom to whichthey are attached form a ring and mean —(CH₂)₃₋₅—;3-6-membered cycloalkyl, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl,wherein said 3-6-membered cycloalkyl is connected through—C₁-C₆-alkylene;3-6-membered heterocycloalkyl, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and—O—C₁-C₄-alkyl, wherein said 3-6-membered heterocycloalkyl is connectedthrough —C₁-C₄-alkylene; -phenyl, unsubstituted or monosubstituted with—OCH₁; wherein said -phenyl is connected through —C₁-C₆-alkylene-; or-pyridyl, unsubstituted, mono- or polysubstituted; wherein said -pyridylis connected through —C₁-C₄-alkylene-:R⁵ means-phenyl, -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl,-pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl,-1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl,-pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl,-indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or-1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of

-   -   —F; —Cl; —Br; —I;    -   —CN; —C₁-C₄-alkyl; —C₁-C₄-alkyl-OH; —CF₃; —C₁-C₄-alkyl-CF₃;        —C₁-C₄-alkyl-C(═O)NH₂; —C₁-C₄-alkyl-C(═O)NHC₁-C₄-alkyl;        —C₁-C₄-alkyl-C(═O)N(C₁-C₄-alkyl)₂-C₁-C₄-alkyl-S(═O)₂—C₁-C₄-alkyl;    -   —C(═O)—C₁-C₃-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂;        —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂;        —C(═O)NH(C₁-C₄-alkyl-OH); —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH);        —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃;    -   —NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH;        —NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂;        —NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl;        —NCH₃C(═O)—C₁-C₄-alkyl;    -   —OH; —O—C₁-C₄-alkyl; —OCF₃; —O—C₁-C₄-alkyl-CO₂H;        —O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; —O—C₁-C₄- alkyl-CONH₂;    -   —S—C₁-C₄-alkyl; —S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and        —S(═O)₂N(C₁-C₄-alkyl)₂;    -   -3-12-membered cycloalkyl, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        3-12-membered cycloalkyl is optionally connected through —CH₂—,        —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—,        —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,        —C(═O)NCH₃—(CH₂)₁₋₃—;    -   -3-12-membered heterocycloalkyl, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        3-12-membered heterocycloalkyl is optionally connected through        —CH₂—, —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—,        —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,        —C(═O)NCH₃—(CH₂)₁₋₃—;    -   -6-14-membered aryl, unsubstituted, mono- or polysubstituted;        wherein said 6-14-membered aryl is optionally connected through        —CH₂—, —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—,        —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,        —C(═O)NCH₃—(CH₂)₁₋₃—; or    -   -5-14-membered heteroaryl, unsubstituted, mono- or        polysubstituted; wherein said 5-14-membered heteroaryl is        optionally connected through —CH₂—, —O—, —NH—, —NCH₃—,        —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—,        —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; and        R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H,

In a particularly preferred embodiment of the compound according to theinvention

R¹ means —H or —CH₃; and/orR² means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted;preferably, R² means —CH₃ or —CH₂CH₃; more preferably, R¹ and R² bothmean —CH₃; and/orR³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —CN, —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₁, —C(═O)NH₂, C(═O)NHCH₁,—C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₂)₂, —NHC(═O)CH₃, —CH₂OH, SOCH₃ andSO₂CH₃; preferably, R³ means -phenyl, -thienyl or -pyridinyl, in eachcase unsubstituted or substituted with —F; more preferably. R³ meansphenyl, unsubstituted; and/orR⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, and —O—C₁-C₄-alkyl; or3-6-membered cycloalkyl, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl,wherein said 3-6-membered cycloalkyl is connected through—C₁-C₆-alkylene; preferably. R⁴ means 3-6-membered cycloalkyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-memberedcycloalkyl is connected through —CH₂— or —CH₂CH₂—; more preferably, R⁴means -cyclobutyl, unsubstituted or monosubstituted with —OH, whereinsaid -cyclobutyl is connected through —CH₂—; and/orR⁵ means -phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl,-thienyl, or imidazo[1,2-a]pyrazine, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F; —Cl; —Br; —I; —CN;—OH; —C₁-C₄-alkyl; —CF₃; -3-12-membered cycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferablycyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably -pyrrolidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl,or -thiomorpholinyl dioxide, in each case saturated, unsubstituted ormonosubstituted with —C₁-C₄-alkyl, -6-14-membered aryl, unsubstituted,mono- or polysubstituted; preferably -phenyl, unsubstituted;—O—C₁-C₄-alkyl; —S—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl;—C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂;—C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂)₁₋₃-3-12-memberedcycloalkyl, saturated or unsaturated, unsubstituted or monosubstitutedwith —OH; preferably —C(═O)NH—(CH₂)₁₋₃-cyclobutyl, saturated orunsaturated, unsubstituted or monosubstituted with —OH;—C(═O)-3-12-membered heterocycloalkyl, saturated or unsaturated,unsubstituted, mono- or polysubstituted; preferably —C(═O)-morpholinyl,saturated, unsubstituted; —S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and—S(═O)₂N(C₁-C₄-alkyl)₂; and/orR¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.

Preferably, the compound according to the invention is selected from thegroup consisting of

SC_3001cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3002cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile SC_3003cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3004cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3005cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3006cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrile SC_3007cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3008cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3009cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3010cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspire[4.5]decan-3-yl]-benzamide SC_3011cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3012cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3013cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3014cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3015cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3016cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide SC_3017cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide SC_3018cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile SC_3019cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3020cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3021cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3022cis-1-(Cyclobutyl-methyl)-8-dimethylamino-2-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3023cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3024cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3025cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3026cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3027cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3028cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide SC_3029cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide SC_3030cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3031cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3032cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide SC_3033cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3034cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3035cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3036cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3037cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3038cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3039cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3040cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3041cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3042cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amideSC_3043cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3044cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3045cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3046cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3047cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3048cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3049cis-1-(Cyclobutyl-methyl)-8-dimethylamino-(6-methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3050cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3051cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-4-carbonitrile SC_3052cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide SC_3053cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3054cis-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3055cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3056cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3057cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetamide SC_3058cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3059cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3060cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3061cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3063cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile SC_3064cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_3065cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3066cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3067cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrile SC_3068cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3069cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile SC_3070cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-pyridine-2-carboxylicacid amide SC_3071cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3072cis-3-[1-(Cyclobuty-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3073cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3074cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylic acid methyl ester SC_3075cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3076cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3077cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3078cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3079cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3080cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3081cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzoic acid methyl ester SC_3082cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3083cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyridin-2-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3084cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3085cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3086cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3087cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl-]-4-methylsulfonyl-benzonitrile SC_3088cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile SC_3089cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide SC_3090cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3091cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2-a]pyrazin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3092cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3093cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile SC_3094cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3096cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3097cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3098cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3099cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3100cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piperazia-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride SC_3101cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3102cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one dihydrochloride SC_3103cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3104cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3105cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3106cis-1-(Cyclopropyl-methyl)-8-methylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3107cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3108cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; formic acid SC_3109cis-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3110cis-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3111cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3112cis-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3113cis-4-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3114cis-4-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3115cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3116cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3117cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3118cis-4-Methoxy-5-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile SC_3119cis-2-(8-Methylamine-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamideSC_3120cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3121cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3122cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3123cis-8-Dimethylamino-3-(2-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3124cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3125trans-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamideSC_3126cis--2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamideSC_3127cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrileSC_3128cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrileSC_3129cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile SC_3130cis-8-Dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3131cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide SC_3132cis-8-[(Cyclopropyl-methyl)-methyl-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3133cis-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3134trans-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrileSC_3135cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrileSC_3136cis-3-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3137cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3138cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3139cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-pyrimidine-2-carboxylic acid amide SC_3140cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carboxylic acid amide SC_3141cis-8-Dimethylamino-3-[2-morpholin-4-yl-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3142cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile SC_3143cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile SC_3144trans-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile SC_3145cis-8-Dimethylamino-3-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3146cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid methyl ester SC_3147cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3148cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3149cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3150cis-8-Dimethylamino-3-(4-fluoro-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3151cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylic acid amide SC_3152cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-isonicotinonitrile SC_3153cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamideSC_3154cis-8-Dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3155cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzonitrileSC_3156cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzonitrile SC_3157cis-8-Dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3158cis-3-[2-(Benzylamino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3159cis-8-Dimethylamino-3-[2-(4-fluorophenyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3160trans-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3161cis-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3162cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3163cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzamide SC_3164cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzamideSC_3165cis-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3166trans-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3167cis-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3168trans-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3169cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-aceticacid SC_3170cis-8-Dimethylamino-8-phenyl-3-(2-piperidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3171cis-8-Dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3172cis-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3173cis-8-Dimethylamino-8-phenyl-3-[2-(piperazine-1-carbonyl)-pyrimidin-5-yl]-1,3-diazaspiro[1.5]decan-2-one SC_3174trans-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3175cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-pyridine-4-carboxylic acid amide SC_3176cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3177cis-3-[2-(Benzothiazol-6-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3178cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3179cis-8-Dimethylamino-3-(6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3180cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-oneSC_3181cis-8-Dimethylamino-8-phenyl-3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3182cis-8-Dimethylamino-3-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3183cis-8-Dimethylamino-8-phenyl-3-(4-phenyl-thiazol-2-yl)-1,3-diazaspiro[4.5]decan-2-oneSC_3184cis-8-Dimethylamino-8-phenyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3185cis-8-Dimethylamino-8-phenyl-3-[2-(3,4,5-trifluoro-phenyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3186cis-8-Dimethylamino-3-o-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3187cis-8-Dimethylamino-3-m-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3188cis-8-Dimethylamino-8-phenyl-3-p-tolyl-1,3-diazaspiro[4.5]decan-2-oneSC_3189cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-oneSC_3190cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one SC_3191cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one SC_3192cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoicacid methyl ester SC_3193cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazapiro[4.5]decan-3-yl)-benzoicacid methyl ester SC_3194cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoicacid methyl ester SC_3195cis-3-(1,3-Benzodioxol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3196cis-8-Dimethylamino-8-phenyl-3-quinolin-5-yl-1,3-diazaspiro[4.5]decan-2-oneSC_3197cis-3-(2,3-Dihydro-1H-indol-6-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3198cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carboxylic acid methyl ester SC_3199cis-8-Dimethylamino-3-(6-methoxy-4-methyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3200cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3201cis-8-Dimethylamino-3-(3-methoxy-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3202cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3203cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrileSC_3204cis-8-Dimethylamino-3-(3-methyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3205cis-8-Dimethylamino-3-(6-methoxy-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3206cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-oneSC_3207cis-3-(1,3-Benzodioxol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3208cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3209cis-8-Dimethylamino-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3210cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3211cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3212cis-8-Dimethylamino-3-[2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3213cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid SC_3214cis-8-Dimethylamino-3-[2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3215cis-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3216trans-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3217cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3218cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3219cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3220cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3221cis-8-Dimethylamnio-3-[2-(2-hydroxy-ethylamino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3222cis-3-[2-(Benzyl-methyl-amino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3223cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylic acidamide SC_3224cis-8-Dimethylamino-3-[2-(1H-indazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3225cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3226cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamideSC_3227cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3228cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3229cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3230cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3231cis-8-Dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-oneSC_3232cis-3-([2,1,3]Benzoxadiazol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3233cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetamideSC_3234cis-8-Dimethylamino-8-phenyl-3-(5-pyridin-4-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-oneSC_3235cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-aceticacid methyl ester SC_3236cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3237cis-3-[2-(3,4-Difluoro-phenyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3238cis-2-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile SC_3239cis-3-(2-Amino-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3240cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-cyclopropanecarboxylic acid amide SC_3241cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetamide SC_3242cis-8-Dimethylamino-8-phenyl-3-(6-piperazin-1-yl-pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3243cis-8-Dimethylamino-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]-decan-2-one SC_3244cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3245cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3246cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3247cis-8-Dimethylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3248cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3249cis-2-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3250cis-8-Dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3251cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carbonitrileSC_3252cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3253cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3254cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3255cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3256cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3257cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one SC_3258cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carbonitrile SC_3259cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_3260cis-8-Dimethylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-oneSC_3261cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one SC_3262cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3263cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3264cis-8-Dimethylamino-3-(3-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3265cis-8-Dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3266cis-8-Dimethylamino-8-phenyl-3-pyridazin-3-yl-1,3-diazaspiro[4.5]decan-2-oneSC_3267cis-3-Methoxy-4-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrileSC_3268cis-8-Dimethylamino-3-(2-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3269cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-oneSC_3270cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3271cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3272cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrileSC_3273cis-8-Dimethylamino-3-(4-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3274cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrileSC_3275cis-8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3276cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3277cis-8-Dimethylamino-3-[2-(morpholin-4-yl-methyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3278cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3279cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylic acid amide SC_3280cis-1-(Cyclopropyl-methyl)-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3281cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-methyl-amino]-acetamide SC_3282cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]amino]-acetamide SC_3283cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3284cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3285cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-thiophene-2-carboxylic acid amide SC_3286cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide SC_3287cis-8-Dimethylamino-8-phenyl-3-(5-phenyl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-oneSC_3288cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3289cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3290cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one SC_3291cis-8-Dimethylamino-8-(4-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one SC_3292cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1) SC_3293cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2) SC_3294cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3295cis-3-[6-(4-Aectyl-piperazin-1-yl)-4-methyl-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3296cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3297cis-8-Dimethylamino-3-(4-methyl-6-pyridin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3298cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3299cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3300cis-8-Dimethylamino-3-isoquinolin-4-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3301cis-8-Dimethylamino-3-isoquinolin-5-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3302cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3303cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-oneSC_3304cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1) SC_3305cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2) SC_3306cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3307cis-3-[2-(3,3-Difluoro-azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3308cis-8-Dimethylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3309cis-8-Methylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3310cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyloxy)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3311cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3312cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrileSC_3313cis-3-[2-(4-Cyclopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3314cis-8-Dimethylamino-3-[4-methyl-2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3315cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carboxylicacid amide SC_3316cis-3-[4-(Azetidin-1-yl)-2-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3317cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamideSC_3318cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3319cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3320cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3321cis-8-Dimethylamino-3-(6-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3322cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3323cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-acetamide SC_3324cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1) SC_3325cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2) SC_3326cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3327cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3328cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-3-carboxylicacid amide SC_3329cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3330cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3331cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3332cis-8-Dimethylamino-3-[4-methyl-6-(3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3333cis-8-Dimethylamino-3-(4-methyl-6-pyridin-2-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3334cis-8-Dimethylamino-3-(4-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3335cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3336cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3337cis-2-[8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3338cis-8-Dimethylamino-3-[2-(2-methyl-1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3339cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methyl-pyrimidin-4-yl]amino]-acetamide SC_3340cis-2-[3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridin-4-yl]-acetamide SC_3341cis-8-Dimethylamino-3-[4-(methylsulfonyl-methyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3342cis-8-Dimethylamino-3-[6-(4-methyl-3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3343cis-8-Dimethylamino-3-(2,4-dimethyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3344cis-8-Dimethylamino-3-[2-(1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; 2,2,2-trifluoro-acetic acid SC_3345cis-8-Dimethylamino-3-[6-[(2-hydroxy-ethyl)-methyl-amino]-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3346cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]triazol-1-yl]-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3347cis-8-Dimethylamino-3-[2-(4-isopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3348cis-8-Dimethylamino-3-[6-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3349cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-nicotinonitrile SC_3350cis-8-Dimethylamino-3-(1-methylsulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3351cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3352cis-8-Dimethylamino-3-(2-hydroxy-benzooxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3353cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyloxy)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3354cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide; 2,2,2-trifluoro-acetic acid SC_3355cis-8-Dimethylamino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3356cis-3-(1-Acetyl-1H-indol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3357cis-8-Dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3358cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-nicotinonitrile SC_3359cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-nicotinonitrileSC_3360cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3361cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-pyridine-3-carboxylic acid amide SC_3362cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-pyridine-3-carboxylic acid amide SC_3363cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-m-tolyl-1,3-diazaspiro[4.5]decan-2-one SC_3364cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-isonicotinonitrileSC_3365cis-8-Dimethylamino-3-[3-fluoro-5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3366cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one SC_3367cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one SC_3368cis-8-Dimethylamino-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3369cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3370cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3371cis-8-Dimethylamino-3-(2-methylamino-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3372cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3373cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-cyclopropanecarboxylic acid amide SC_3374cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylic acid amide SC_3375cis-3-[4,6-Bis-(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3376cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-6-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3377cis-8-Dimethylamino-3-(2-morpholin-4-yl-quinazolin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3378cis-8-[Methyl-(oxetan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3379cis-3-(1-Acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3380cis-8-Dimethylamino-8-phenyl-3-quinazolin-6-yl-1,3-diazaspiro[4.5]decan-2-oneSC_3381cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-(2-oxo-1,3-dihydro-indol-4-yl)-isonicotinonitrile SC_3382cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylic acid amide SC_3383cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,2-trimethyl-propionamide SC_3384cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3385cis-8-Dimethylamino-3-(2-morpholin-4-yl-1H-benzoimidazol-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3386cis-8-Dimethylamino-8-(3-fluoro-5-methyl-phenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3387cis-8-Dimethylamino-3-[6-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3388cis-8-Dimethylamino-8-(3-hydroxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3389cis-3-[6-(Azetidin-1-yl)-5-(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3390cis-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phennyl-1,3-diazaspiro[4.5]decan-3-yl]-isonicotinonitrile SC_3391cis-3-[3,5-Bis(trifluoromethyl)-pyridin-2-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3392cis-8-Dimethylamino-3-(5-fluoro-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3393cis-8-(3-Chlorophenyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3394cis-8-Dimethylamino-3-[5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3395cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-[1,3,4]thiadiazol-2-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3396cis-8-Dimethylamino-3-(2-oxo-1,3-dihydro-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3397cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-1H-benzoimidazol-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3398cis-8-Dimethylamino-3-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3399cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3400cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3401cis-1-(Cyclobutyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3402cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3403cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3404cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3405cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-oneSC_3406cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-oneSC_3407cis-8-Methylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3408cis-3-[5-(Azetidin-1-yl)-3-methyl-pyridin-2-yl]-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3409cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3410cis-3-(6-(azetidin-1-yl)-4-fluoropyridin-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3411cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3412cis-3-(1-(cyclopropanecarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3413cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3414cis-3-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3415cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3416cis-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-oneSC_3417cis-2-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide SC_3418cis-2-(5-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamideSC_3419cis-8-(dimethylamino)-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3420cis-8-(dimethylamino)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3421cis-8-(dimethylamino)-8-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3422cis-8-(dimethylamino)-8-phenyl-3-(2-(pyridazin-4-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3423cis-8-(dimethylamino)-3-(2-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3424cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3425cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-morpholino-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3426cis-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3427cis-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one SC_3428cis-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3429cis-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3430cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(methylsulfonyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3431cis-8-(dimethylamino)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3432cis-3-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3433cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(oxetan-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3434cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-(methylsulfonyl)ethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3435cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-methyl-2-(methylamino)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3436cis-3-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3437cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide SC_3438cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylpivalamide SC_3439cis-3-(4-(azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3440cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(oxetan-3-ylmethoxy)-2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3441cis-3-(2-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3442cis-3-(2-cyclopropyl-4-((2-hydroxyethyl)(methyl)amino)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-oneand the physiologically acceptable salts thereof.

According to the invention, unless expressly stated otherwise,“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can belinear or branched, saturated or unsaturated, Linear saturated alkylincludes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl,Examples of branched saturated alkyl include but are not limited toiso-propyl, sec-butyl, and tert-butyl, Examples of linear unsaturatedalkyl include but are not limited to vinyl, propenyl, allyl, andpropargyl.

According to the invention, unless expressly stated otherwise.“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can beunsubstituted, mono- or polysubstituted. Examples of substituted alkylinclude but are not limited to —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—CH₂CH₂S(═O)₂CH₃, —CH₂C(═O)NH₂, —C(CH₃)₂C(═O)NH₂, —CH₂C(CH₁)₂C(═O)NH₂,and —CH₂CH₂C(═O)N(CH₃)₂.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of saturatedalkylene include but are not limited to —CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₂)—, —CH(CH₃)—CH(CH₃)—, —C(CH₃)₂CH₂—,—CH₂C(CH₃)₂—, —CH(CH₃)C(CH₃)₂—, —C(CH₃)₂CH(CH₃)—, C(CH₃)₂C(CH₃)₂—,—CH₂CH₂CH₂—, and —C(CH₃)₂CH₂CH₂—. Examples of unsaturated alkyleneinclude but are not limited to —CH═CH—, —C≡C—, —C(CH₁)═CH—, —CH═C(CH₁)—,—C(CH₁)═C(CH₃)—, —CH₂CH═CH—, —CH═CHCH₂—, —CH═CH—CH═CH—, and —CH═CH—C═C—.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of substituted—C₁-C₄-alkylene- include but are not limited to —CHF—, —CF₂—, —CHOH— and—C(═O)—.

According to the invention, moieties may be connected through—C₁-C₆-alkylene-, i.e. the moieties may not be directly bound to thecore structure of compound according to general formula (I), but may beconnected to the core structure of compound according to general formula(I) or its periphery through a —C₁-C₆-alkylene-linker.

According to the invention, “3-12-membered cycloalkyl moiety” means anon-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to12 ring carbon atoms but no heteroatoms in the ring. Examples ofpreferred saturated 3-12-membered cycloalkyl moieties according to theinvention include but are not limited to cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, anddecaline. Examples of preferred unsaturated 3-12-membered cycloalkylmoiety moieties according to the invention include but are not limitedto cyclopropene, cyclobutene, cyclopentene, cyclopentadiene,cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene. The3-12-membered cycloalkyl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 6-14-memberedaryl moiety, unsubstituted, mono- or polysubstituted, and/or with a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 3-12-membered heterocycloalkyl moieties includebut are not limited to octahydro-1H-indol, decahydroquinoline,decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, anddecahydroquinoxalin, which in each case are connected through the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 6-14-membered aryl moieties include but are notlimited to 2,3-dihydro-1H-indene and tetraline, which in each case areconnected through the 3-12-membered cycloalkyl moiety. Examples of3-12-membered cycloalkyl moieties condensed with 5-14-memberedheteroaryl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 3-12-membered cycloalkyl moiety.

According to the invention, the 3-12-membered cycloalkyl moiety mayoptionally be connected through —C₁-C₆-alkylene-, i.e. the 3-12-memberedcycloalkyl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene- linker. Examples include but are not limited to—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl.—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, and—CH₂CH₂-cyclohexyl.

According to the invention, unless expressly stated otherwise, the3-12-membered cycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered cycloalkylmoieties include but are not limited to —CH₂-1-hydroxy-cyclobutyl.

According to the invention, “3-12-membered heterocycloalkyl moiety”means a non-aromatic, monocyclic, bicyclic or tricyclic moietycomprising 3 to 12 ring atoms, wherein each cycle comprisesindependently of one another 1, 2, 3, 4 or more heteroatomsindependently of one another selected from the group consisting ofnitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S(═O) or(S(═O)₂), whereas the remaining ring atoms are carbon atoms, and whereasbicyclic or tricyclic systems may share common heteroatom(s). Examplesof preferred saturated 3-12-membered heterocycloalkyl moieties accordingto the invention include but are not limited to aziridin, azetidine,pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine,triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane,tetrahydropyrane, thiirane, thietane, tetrahydrothiophene, diazepane,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,thiadiazolidine, morpholine, thiomorpholine. Examples of preferredunsaturated 3-12-membered heterocycloalkyl moiety moieties according tothe invention include but are not limited to oxazoline, pyrazoline,imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran.The 3-12-membered heterocycloalkyl moiety, which is bonded to thecompound according to the invention in its periphery may optionally becondensed with a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; and/or with a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered heterocycloalkyl moieties. Examples of 3-12-memberedheterocycloalkyl moieties condensed with 3-12-membered cycloalkylmoieties include but are not limited to octahydro-1H-indol,decahydroquinoline, decahydroisoquinoline,octahydro-2H-benzo[b][1,4]-oxazin, and decahydroquinoxalin, which ineach case are connected through the 3-12-membered heterocycloalkylmoiety. An examples of a 3-12-membered heterocycloalkyl moiety condensedwith a 6-14-membered aryl moiety includes but is not limited to1,2,3,4-tetrahydroquinoline, which is connected through the3-12-membered heterocycloalkyl moiety. An example of a 3-12-memberedheterocycloalkyl moiety condensed with a 5-14-membered heteroarylmoieties includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 3-12-membered heterocycloalkyl moiety.

According to the invention, the 3-12-membered heterocycloalkyl moietymay optionally be connected through —C₁-C₆-alkylene-, i.e. the3-12-membered heterocycloalkyl moiety may not be directly bound to thecompound according to general formula (I) but may be connected theretothrough a —C₁-C₆-alkylene- linker. Said linker may be connected to acarbon ring atom or to a hetero ring atom of the 3-12-memberedheterocycloalkyl moiety. Examples include but are not limited to—CH₂-oxetane, —CH₂-pyrrolidine, —CH₂-piperidine, —CH₂-morpholine,—CH₂CH₂-oxetane, —CH₂CH₂-pyrrolidine, —CH₂CH₂-piperidine, and—CH₂CH₂-morpholine.

According to the invention, unless expressly stated otherwise, the3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered heterocycloalkylmoieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-,3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl,3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl,-tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.

According to the invention. “6-14-membered aryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring carbon atoms but no heteroatoms in the ring. Examples of preferred6-14-membered aryl moieties according to the invention include but arenot limited to benzene, naphthalene, anthracen, and phenanthren. The6-14-membered aryl moiety, which is bonded to the compound according tothe invention, in its periphery may optionally be condensed with a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 6-14-membered aryl moieties condensed with 3-12-memberedcycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indeneand tetraline, which in each case are connected through the6-14-membered aryl moiety. An example of a 6-14-membered aryl moietycondensed with a 3-12-membered heterocycloalkyl moiety includes but isnot limited to 1,2,3,4-tetrahydroquinoline, which is connected throughthe 6-14-membered aryl moiety. Examples of 6-14-membered aryl moietiescondensed with 5-14-membered heteroaryl moieties include but are notlimited to quinoline, isoquinoline, phenazine and phenoxacine, which ineach case are connected through the 6-14-membered aryl moiety.

According to the invention, the 6-14-membered aryl moiety may optionallybe connected through —C₁-C₆-alkylene-, i.e. the 6-14-membered arylmoiety may not be directly bound to the compound according to generalformula (I) but may be connected thereto through a —C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ring atom or to ahetero ring atom of the 6-14-membered aryl moiety. Examples include butare not limited to —CH₂—C₆H₅, —CH₂CH₂—C₆H₅ and —CH═CH—C₆H₅.

According to the invention, unless expressly stated otherwise, the6-14-membered aryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 6-14-membered aryl moietiesinclude but are not limited to 2-fluorophenyl, 3-fluorophenyl,2-methoxyphenyl and 3-methoxyphenyl.

According to the invention, “5-14-membered heteroaryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring atoms, wherein each cycle comprises independently of one another 1,2, 3, 4 or more heteroatoms independently of one another selected fromthe group consisting of nitrogen, oxygen and sulfur, whereas theremaining ring atoms are carbon atoms, and whereas bicyclic or tricyclicsystems may share common heteroatom(s). Examples of preferred5-14-membered heteroaryl moieties according to the invention include butare not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole,furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine,pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine,1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine. The5-14-membered heteroaryl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 5-14-membered heteroaryl moieties condensed with3-12-membered cycloalkyl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 5-14-membered heteroaryl moiety. Anexamples of a 5-14-membered heteroaryl moiety condensed with a3-12-membered heterocycloalkyl moiety includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 5-14-membered heteroaryl moiety. Examples of 5-14-memberedheteroaryl moieties condensed with 6-14-membered aryl moieties includebut are not limited to quinoline, isoquinoline, phenazine andphenoxacine, which in each case are connected through the 5-14-memberedheteroaryl moiety.

According to the invention, the 5-14-membered heteroaryl moiety mayoptionally be connected through —C₁-C₆-alkylene-. i.e. the 5-14-memberedheteroaryl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene- linker. Said linker may be connected to a carbon ringatom or to a hetero ring atom of the 5-14-membered heteroaryl moiety.Examples include but are not limited to —CH₂-oxazole, —CH₂-isoxazole,—CH₂-imidazole, —CH₂-pyridine, —CH₂-pyrimidine, —CH₂-pyridazine,—CH₂CH₂-oxazole, —CH₂CH₂-isoxazole, —CH₂CH₂-imidazole, —CH₂CH₂-pyridine,—CH₂CH₂-pyrimidine, and —CH₂CH₂-pyridazine.

According to the invention, unless expressly stated otherwise, the5-14-membered heteroaryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of 5-14-membered heteroaryl moieties includebut are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl,3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl,2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl,3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl,4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and2-methoxy-6-pyrazinyl.

Preferably, the compound according to the invention has a structureaccording to general formula (I′)

wherein R¹ to R⁵, R¹¹ to R²⁰ are defined as above.

or a physiologically acceptable salt thereof.

In one preferred embodiment, the excess of the cis-isomer so designatedis at least 50% de, more preferably at least 75% de, yet more preferablyat least 90% de, most preferably at least 95% de and in particular atleast 99% de.

In a preferred embodiment, the compound according to the invention has astructure according to general formula (IX) or (X)

whereinR² means —H or —CH₃;R³ means -phenyl or -3-fluorophenyl:R^(C) means —H or —OH;R^(E) means —H, —CH₃, —F, —CF₃, -cyclopropyl, -aziridinyl, —OH;—O—C₁-C₄-alkyl; —OCF₃; —O—C₁-C₆-alkyl-CO₂H;—O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; or —O—C₁-C₄-alkyl-CONH₂;R^(F) means—CF₃, -cyclopropyl, —S(═O)₂CH₃,—NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH;—NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂;—NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl;—NCH₃C(═O)—C₁-C₄-alkyl;-6-14-membered aryl, unsubstituted, mono- or polysubstituted; or-5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted;U means=CH— or ═N—; andV means=CH— or ═N—;or a physiologically acceptable salt thereof

In a preferred embodiment, the compound according to the invention has astructure according to general formula (XI)

whereinR² means —H or —CH₃:R³ means -phenyl or -3-fluorophenyl;R^(H) means—CN; —C₁-C₄-alkyl; —CF₃; —C₁-C₄-alkyl-C(═O)NH₂;—C₁-C₄-alkyl-S(═O)₂—C₁-C₁-alkyl; —C(═O)—C₁-C₄-alkyl; —C(═O)OH;—C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —C(═O)NH(C₁-C₄-alkyl-OH);—C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃;-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,mono- or polysubstituted; wherein said 3-12-membered cycloalkyl isoptionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—,—NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,—C(═O)NCH₃—(CH₂)₁₋₃—; or-3-12-membered heterocycloalkyl, saturated or unsaturated,unsubstituted, mono- or polysubstituted; 6-14-membered aryl,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—,—NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—,—C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—;R^(G) meansCF₃, —S(═O)₂CH₃;—NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH;—NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂;—NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl;—NCH₃C(═O)—C₁-C₄-alkyl;-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,mono- or polysubstituted; wherein said 3-12-membered cycloalkyl isoptionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—,—NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,—C(═O)NCH₃—(CH₂)₁₋₃—; or-3-12-membered heterocycloalkyl, saturated or unsaturated,unsubstituted, mono- or polysubstituted, 6-14-membered aryl,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—,—NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(O)—, —NCH₃C(═O)—,—C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—;or a physiologically acceptable salt thereof.

In a preferred embodiment, the compounds according to the invention arein the form of the free bases.

In another preferred embodiment, the compounds according to theinvention are in the form of the physiologically acceptable salts.

For the purposes of the description, a “salt” is to be understood asbeing any form of the compound in which it assumes an ionic form or ischarged and is coupled with a counter-ion (a cation or anion) or is insolution. The term is also to be understood as meaning complexes of thecompound with other molecules and ions, in particular complexes whichare associated via ionic interactions. Preferred salts arephysiologically acceptable, in particular physiologically acceptablesalts with anions or acids or also a salt formed with a physiologicallyacceptable acid.

Physiologically acceptable salts with anions or acids are salts of theparticular compound in question with inorganic or organic acids whichare physiologically acceptable, in particular when used in humans and/ormammals. Examples of physiologically acceptable salts of particularacids include but are not limited to salts of hydrochloric acid,sulfuric acid, and acetic acid.

The invention also includes isotopic isomers of a compound according tothe invention, wherein at least one atom of the compound is replaced byan isotope of the respective atom which is different from the naturallypredominantly occurring isotope, as well as any mixtures of isotopicisomers of such a compound. Preferred isotopes are ²H (deuterium). ³H(tritium), ¹³C and ¹⁴C.

Certain compounds according to the invention are useful for modulating apharmacodynamic response from one or more opioid receptors (mu, delta,kappa, NOP/ORL-1) either centrally or peripherally, or both. Thepharmacodynamic response may be attributed to the compound eitherstimulating (agonizing) or inhibiting (antagonizing) the one or morereceptors. Certain compounds according to the invention may antagonizeone opioid receptor, while also agonizing one or more other receptors.Compounds according to the invention having agonist activity may beeither full agonists or partial agonists.

As used herein, compounds that bind to receptors and mimic theregulatory effects of endogenous ligands are defined as “agonists”.Compounds that bind to a receptor but produce no regulatory effect, butrather block the binding of ligands to the receptor, are defined as“antagonists”.

In certain embodiments, the compounds according to the invention areagonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or deltaopioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.

The compounds according to the invention potently bind to the MOP and/orKOP and/or DOP and/or NOP receptors.

The compounds according to the invention can be modulators at the MOPand/or KOP and/or DOP and/or NOP receptors, and therefore the compoundsaccording to the invention can be used/administered to treat,ameliorate, or prevent pain.

In some embodiments, the compounds according to the invention areagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are agonists of the MOP and/or KOPand/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention areantagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are antagonists of the MOP and/orKOP and/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor, and (ii) agonist activity atone or more of the MOP. KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor, and (ii) antagonist activityat one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor, and (ii) agonist activityat one or more of the MOP. KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor, and (ii) antagonistactivity at one or more of the MOP. KOP, and DOP receptors.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the NOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor.    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor,    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor,    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor, or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the MOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor,    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        KOP receptor.    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        DOP receptor,    -   can be regarded as opioid pan agonists, i.e. have agonist        activity at the NOP receptor as well as agonist activity at the        MOP receptor as well as agonist activity at the KOP receptor as        well as agonist activity at the DOP receptor,    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor.    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        DOP receptor, or    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the KOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor.    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        MOP receptor.    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        DOP receptor.    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor,    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        DOP receptor, or    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor,    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor,    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor, or    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the KOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor,    -   have agonist activity at the KOP receptor, but no significant        activity at the NOP receptor.    -   have agonist activity at the KOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor,    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor, or    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveagonist activity at the MOP receptor, agonist activity at the KOPreceptor, and antagonist activity at the DOP receptor. In someembodiments, preferably with respect to receptors of the peripheralnervous system, the compounds according to the invention

-   -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor,    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as agonist activity at the NOP        receptor.    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as antagonist activity at the NOP        receptor, or    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor, no significant activity at the NOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor,    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor.    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor.    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor,    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor, or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveantagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor.    -   have antagonist activity at the NOP receptor, but no significant        activity at the KOP receptor,    -   have antagonist activity at the NOP receptor, but no significant        activity at the DOP receptor.    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor.    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor, or    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have antagonistactivity at the NOP receptor as well as agonist activity at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe central nervous system, the compounds according to the invention

-   -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor,    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor,    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor, or    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

For the purpose of the specification, “no significant activity” meansthat the activity (agonist/antagonist) of the given compound at thisreceptor is lower by a factor of 1000 or more compared to its activity(agonist/antagonist) at one or more of the other opioid receptors.

A further aspect of the invention relates to the compounds according tothe invention as medicaments.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of pain. A further aspect of theinvention relates to a method of treating pain comprising theadministration of a pain alleviating amount of a compound according tothe invention to a subject in need thereof, preferably to a human. Thepain is preferably acute or chronic. The pain is preferably nociceptiveor neuropathic.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of neurodegenerative disorders,neuroinflammatory disorders, neuropsychiatric disorders, and substanceabuse/dependence. A further aspect of the invention relates to a methodof treating any one of the aforementioned disorders, diseases orconditions comprising the administration of a therapeutically effectiveamount of a compound according to the invention to a subject in needthereof, preferably to a human.

Another aspect of the invention relates to a pharmaceutical compositionwhich contains a physiologically acceptable carrier and at least onecompound according to the invention.

Preferably, the composition according to the invention is solid, liquidor pasty; and/or contains the compound according to the invention in anamount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, basedon the total weight of the composition.

The pharmaceutical composition according to the invention can optionallycontain suitable additives and/or auxiliary substances and/or optionallyfurther active ingredients.

Examples of suitable physiologically acceptable carriers, additivesand/or auxiliary substances are fillers, solvents, diluents, coloringsand/or binders. These substances are known to the person skilled in theart (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Phamazie, Kosmetikand angrenzende Gebiete, Editio Cantor Aulendoff).

The pharmaceutical composition according to the invention contains thecompound according to the invention in an amount of preferably from0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet morepreferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. %and in particular from 2.5 to 60 wt. %, based on the total weight of thepharmaceutical composition.

The pharmaceutical composition according to the invention is preferablyfor systemic, topical or local administration, preferably for oraladministration.

Another aspect of the invention relates to a pharmaceutical dosage fontwhich contains the pharmaceutical composition according to theinvention.

In one preferred embodiment, the pharmaceutical dosage form according tothe invention is produced for administration twice daily, foradministration once daily or for administration less frequently thanonce daily. Administration is preferably systemic, in particular oral.

The pharmaceutical dosage form according to the invention can beadministered, for example, as a liquid dosage form in the form ofinjection solutions, drops or juices, or as a semi-solid dosage form inthe form of granules, tablets, pellets, patches, capsules,plasters/spray-on plasters or aerosols. The choice of auxiliarysubstances etc. and the amounts thereof to be used depend on whether theform of administration is to be administered orally, perorally,parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or locally, forexample to the skin, the mucosa or into the eyes.

Pharmaceutical dosage forms in the form of tablets, dragees, capsules,granules, drops, juices and syrups are suitable for oral administration,and solutions, suspensions, readily reconstitutable dry preparations andalso sprays are suitable for parenteral, topical and inhalatoryadministration. Compounds according to the invention in a depot, indissolved form or in a plaster, optionally with the addition of agentspromoting penetration through the skin, are suitable percutaneousadministration preparations.

The amount of the compounds according to the invention to beadministered to the patient varies in dependence on the weight of thepatient, on the type of administration, on the indication and on theseverity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg,preferably from 0.001 mg/kg to 10 mg/kg, of at least one compoundaccording to the invention is administered.

Another aspect of the invention relates to a process for the preparationof the compounds according to the invention. Suitable processes for thesynthesis of the compounds according to the invention are known inprinciple to the person skilled in the art.

Preferred synthesis routes are described below:

The compounds according to the invention can be obtained via differentsynthesis routes. Depending on the synthesis route, differentintermediates are prepared and subsequently further reacted.

In a preferred embodiment, the synthesis of the compounds according tothe invention proceeds via a synthesis route which comprises thepreparation of an intermediate according to general formula (IIIa):

wherein R¹, R² and R³ are defined as above.

In another preferred embodiment, the synthesis of the compoundsaccording to the invention proceeds via a synthesis route whichcomprises the preparation of an intermediate according to generalformula (IIIb):

wherein R¹, R² and R³ are defined as above and PG is a protecting group.

Preferably the protecting group is -p-methoxybenzyl. Therefore, inanother preferred embodiment, the synthesis of the compounds accordingto the invention proceeds via a synthesis route which comprises thepreparation of an intermediate according to general formula (IIIc):

wherein R¹, R² and R³ are defined as above.

As already indicated, in general formula (IIIc), the -p-methoxybenzylmoiety represents a protecting group which can be cleaved in the courseof the synthesis route.

In yet another preferred embodiment, the synthesis of the compoundsaccording to the invention proceeds via a synthesis route whichcomprises the preparation of

-   -   an intermediate according to general formula (IIIa) and        according to general formula (IIIb); or    -   an intermediate according to general formula (IIIa) and        according to general formula (IIIc); or    -   an intermediate according to general formula (IIIb) and        according to general formula (IIIc); or    -   an intermediate according to general formula (IIIa), according        to general formula (IIIb) and according to general formula        (IIIc).

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

EXAMPLES

“RT” means room temperature (23±7° C.), “M” are indications ofconcentration in mol/l, “aq.” means aqueous, “sat.” means saturated,“sol.” means solution. “conc.” means concentrated.

FURTHER ABBREVIATIONS

brine saturated aqueous sodium chloride solutionCC column chromatographycHex cyclohexanedba dibenzylideneacetoneDCM dichloromethane

DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide

Et ethylether diethyl etherEE ethyl acetateEtOAc ethyl acetateEtOH ethanolh hour(s)H₂O waterHATUO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateLDA lithium diisoproylamideMe methylm/z mass-to-charge ratioMcOH methanolMeCN acetonitrilemin minutesMS mass spectrometry

NBS N-bromosuccinimide NIS N-iodosuccinimide

NEt₃ triethylaminePE petroleum ether (60-80° C.)RM reaction mixtureRT room temperatureTFA trifluoroacetic acidT3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxidetBME tert-butyl methyl etherTHE tetrahydrofuranev/v volume to volumew/w weight to weightXantphos 4,5-bis(dipheylphosphino)-9,9-dimethylxanthene

The yields of the compounds prepared were not optimised. Alltemperatures are uncorrected.

All starting materials, which are not explicitly described, were eithercommercially available (the details of suppliers such as for exampleAcros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge,Merck, Sigma, TCI, Oak-wood, etc. can be found in the Symyx® AvailableChemicals Database of MDL, San Ramon, US or the SciFinder®, Database ofthe ACS, Washington D.C., US, respectively, for example) or thesynthesis thereof has already been described precisely in the specialistliterature (experimental guidelines can be found in the Reaxys® Databaseof Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS,Washington D.C., US, respectively, for example) or can be prepared usingthe conventional methods known to the person skilled in the an.

The mixing ratios of solvents or eluents for chromatography arespecified in v/v.

All the intermediate products and exemplary compounds were analyticallycharacterised by mass spectrometry (MS, m/z for [M+H]⁺). In addition¹H-NMR and ¹³C spectroscopy was carried out for all the exemplarycompounds and selected intermediate products.

Remark Regarding Stereochemistry

CIS refers to the relative configuration of compounds described herein,in which both nitrogen atoms are drawn on the same face of thecyclohexane ring as described in the following exemplary structure. Twodepictions are possible:

TRANS refers to compounds, in which both nitrogen atoms are on oppositefaces of the cyclohexane ring as described in the following exemplarystructure. Two depictions are possible:

Synthesis of Intermediates

Synthesis of INT-600:5-(cis-8-(Dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4,5]decan-3-yl)pyrimidine-2-carbonitrile

Cs₂CO₃ (1.1 g, 3.66 mmol) was added to the solution ofCIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)(0.5 g, 1.83 mmol), Xanthphos (0.158 g, 0.274 mmol), Pd₂(dba)₃ (0.083 g,0.091 mmol) and 5-bromopyrimidine-2-carbonitrile (0.52 g, 2.74 mmol) in1,4-dioxane (20 mL) under argon atmosphere. The reaction mixture wasstirred for 16 h at 90° C., then cooled to RT and concentrated underreduced pressure. The residue was suspended in EtOAc (20 mL) andfiltered through a plug of celite. The filtrate was concentrated underreduced pressure and the resulting residue was purified by flashchromatography on silica gel to afford5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile(INT-600) (0.4 g) as a white solid.

Synthesis of INT-799:CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4,5]decan-2-one

Step 1:CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaOH (1.42 g, 35.5 mmol) was added to a solution ofCIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazasprio[4.5]decan-2-one(INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere andthe reaction mixture was stirred at 80° C. for 30 min.((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was addedand stirring was continued for 2 days at 80° C. The reaction completionwas monitored by TLC. The reaction mixture was diluted with water (500mL) and extracted with diethyl ether (4×300 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (230-400mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford2.5 g (59%) ofCIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(TLC system: 10% MeOH in DCM; Rf: 0.8).

Step 2:CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

TFA (12 mL) was added toCIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70°C. for 6 h. The reaction completion was monitored by LCMS. The reactionmixture was concentrated under reduced pressure. To the residue sat. aq.NaHCO₃ was added (until pH 10) and the organic product was extractedwith DCM (3×150 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (230-400 mesh silica gel; 5% MeOHin DCM as eluent) to afford 500 mg (33%) ofCIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H]⁺ 358.2

Synthesis of INT-951:CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile

Step 1:1-((CIS8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (5 g, 12.72 mmol) in DMF (100 mL) at 0° C. portionwise over 10min. 1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) wasadded dropwise over 10 minutes at 0° C. The reaction mixture was allowedto stir at RT for 3 h, then quenched with water and the organic productwas extracted with ethyl acetate (3×200 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 5 g (crude) of1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrileas gummy brown liquid. The material was used for the next step withoutfurther purification.

Step 2:1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide

TFA (100 mL) was added to1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile(5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture wasstirred at RT for 2 days. The reaction mixture was concentrated invacuo. To the residue sat. aq. NaHCO₃ was added (until pH 10) and theorganic product was extracted with dichloromethane (3×150 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 3.5 g (crude) of1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide. The material was used for the next step withoutfurther purification.

Step 3:1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

Thionyl chloride (35 mL) was added to1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide(3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at refluxfor 2 h. The reaction mixture was concentrated in vacuo. To the residuesat. aq. NaHCO₁ was added (until pH 10) and the organic product wasextracted with dichloromethane (3×150 mL). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by column chromatography to afford 1.3 g (34% after threesteps) ofCIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile(INT-951). [M+H]⁺ 1367.2.

Synthesis of INT-952:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (10 g, 25 mmol) in THF (500 mL) was addedKOtBu (7.1 g, 63 mmol) at 50° C. The reaction mixture was heated up toreflux, cyclobutylmethylbromide (11.3 g, 76 mmol) was added in oneportion, and stirring was continued at reflux for 12 h. KOtBu (7.1 g)and cyclobutylmethylbromide (11.3 g) were added again. The reactionmixture was allowed to stir another 2 h at reflux, then cooled to RT,diluted with water (150 mL) and the layers partitioned. The aqueouslayer was extracted with EtOAc (3×300 mL). The combined organic layerswere dried over Na₂SO₄ and then concentrated in vacuo. The residue wasfiltered through a plug of silica gel using a DCM/MeOH (19/1 v/v)mixture. The filtrate was concentrated in vacuo and the resulting solidwas recrystallized from hot ethanol to yield 7.8 g ofCIS-1-(cyclobutyl-methyl)-8-diethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-952). [M+H]⁺ 461.3.

Synthesis of INT-953:CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one

To a stirred solution of3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g, 60%dispersion in oil, 36.14 mmol) at RT. The reaction mixture was stirredfor 10 min. bromomethylcyclobutane (3 ml, 26.5 mmol) was added dropwiseand stirring was continued for 50 h. TLC analysis showed completeconsumption of the starting material. The reaction mixture was quenchedwith sat. aq. NH₄Cl (50 ml) and extracted with EtOAc (3×200 ml). Thecombined organic phase was dried over Na₂SO₄ and concentrated underreduced pressure. The resulting residue was purified columnchromatography (neutral aluminum oxide, EtOAc—petroleum ether (2:8)) togive1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(2.4 g, 50%, white solid). TLC system: EtOAc—pet ether (6:4):R_(f)=0.48.

Step 2:1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione

To a stirred solution ofl-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(1 g, 2.5 mmol) in MeOH (7 ml) was added 10% aq. HCl (8 ml) at 0° C. Thereaction mixture was warmed up to RT and stirred for 16 h. TLC analysisshowed complete consumption of the starting material. The reactionmixture was quenched with sat. aq. NaHCO₃ (30 ml) and extracted withEtOAc (3×50 ml). The combined organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, 230-400 mesh. EtOAc—pet ether(1:3)→(3:7)) to give1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione(650 mg, 73%, colorless viscous oil). TLC system: EtOAc—pet ether (6:4):R_(f)=0.40.

Step 3:1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

To a stirred solution of N-isobutyl-N-methylamine (1.34 ml, 11.23 mmol)and MeOH/H₂O (8 ml, 1:1, v/v) was added 4N aq. HCl (1.5 ml) and thereaction mixture was stirred for 10 min at 0° C. (ice bath). A solutionof1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione(1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol) were addedand the reaction mixture was stirred at 45° C. for 20 h. TLC analysisshowed complete consumption of the starting material. The reactionmixture was diluted with water (30 ml), extracted with EtOAc (3×30 ml),the combined organic phase was dried over Na₂SO₄ and concentrated underreduced pressure to give1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(1.3 g, viscous yellow oil). TLC system: EtOAc—pet ether (1:1);R_(f)=0.45. The product was used for the next step without additionalpurification.

Step 4:CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containingl-cyclobutylmethyl)-8-isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(1.3 g, 2.81 mmol) was cooled in an ice bath (˜0° C.) and a solution ofphenylmagnesium bromide (26 ml, ˜2M in THF) was added slowly at 0° C.-5°C. The ice bath was removed and the reaction mixture was stirred for 30min, then diluted with sat. aq. NH₄Cl (25 ml) and extracted with EtOAc(4×30 ml). The combined organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure to give pale yellow viscous oil.This residue was purified by column chromatography (silica gel, 230-400mesh, eluent: EtOAc—pet ether (15:85)→(2:4)) to giveCIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(135 mg, 10%, white solid). TLC system: EtOAc—pet ether (1:1). R_(f)=0.6

Step 5:CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containingCIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(130 mg, 0.25 mol) was cooled in an ice bath and a mixture of TFA/CH₂Cl₂(2.6 ml, 1:1, v/v) was added slowly at 0° C.-5° C. The reaction mixturewas warmed to RT and stirred for 20 h, then quenched with methanolic NH₃(10 ml, ˜10% in MeOH) and concentrated under reduced pressure to givepale yellow viscous oil. This residue was purified twice by columnchromatography (silica gel, 230-400 mesh, eluent: MeOH—CHCl₃(1:99)→(2:98)) to giveCIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-953) (65 mg, 66%, white solid). TLC system: MeOH—CHCl₃ (5:95):R_(f)=0.25; [M+H]⁺ 384.3

Synthesis of INT-958: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate

KOtBu (57.0 g, 508.4 mmol) was added to the solution of2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate(89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h atRT. The reaction mixture was quenched with sat. aq. NH₄Cl and extractedwith EtOAc (2×500 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to afford 68.0g (60%; crude) of ethyl5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid(TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).

Step 2: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate(68.0 g, 250.0 mmol) was added to a mixture of conc. aq. HCl and glacialacetic acid (170 mL/510 mL) at 0° C. The reaction mixture was heated to100° C. for 16 h. All volatiles were evaporated under reduced pressure.The residue was diluted with sat. aq. NaHCO₃ and extracted with ethylacetate (3×300 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to afford 44.0g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile INT-958 as abrown solid (TLC system: 50% ethyl acetate in pet ether, Rf: 0.45).[M+H]⁺ 201.1

Synthesis of INT-961: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Step 1: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

A solution of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958)(44.0 g, 220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2g, 22.0 mmol) in toluene (450 mL) was heated to 120° C. for 16 h usingDean Stark apparatus. All volatiles were evaporated under reducedpressure. The residue was diluted with sat. aq. NaHCO₃ and extractedwith ethyl acetate (3×300 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toafford 45.0 g (85%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a lightbrown solid (TLC system: 50% ethyl acetate in petroleum ether, Rf:0.55).

Step 2: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide

Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq. H₂O₂ (210.0 mL,1844.2 mmol) were added to the solution of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0 g,184.42 mmol) in DMSO (450 mL) at 0° C. and the resulting mixture wasstirred at RT for 14 h. The reaction mixture was diluted with water (1.5L) and stirred for 1 h. The precipitated solid was separated byfiltration, washed with water, petroleum ether and dried under reducedpressure to get 32.0 g (66%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a whitesolid. (TLC system: 10% MeOH in DCM R_(f): 0.35).

Step 3: methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate

A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide(25.0 g, 95.41 mmol), sodium hypochlorite (5 wt % aq. solution, 700 mL,477.09 mmol) and KF—Al₂O₃ (125.0 g) in methanol (500 mL) was heated to80° C. for 16 h. The reaction mixture was filtered through celite andthe solid residue was washed with methanol. The combined filtrate wasconcentrated under reduced pressure. The residue was diluted with waterand extracted with ethyl acetate (3×500 mL). The combined organic layerwas washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to afford 18.0 g (66%) of methyl8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light brownsolid. (TLC system: 5% MeOH in DCM R_(f): 0.52.)

Step 4: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine

A suspension of methyl8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g, 61.64mmol) in 10 wt % aq. NaOH (200 mL) was heated to 100° C. for 24 h. Thereaction mixture was filtered through celite pad, the solid residue waswashed with water and the combined filtrate was extracted with EtOAc(4×200 mL). The combined organic layer washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to afford 12.5 g (88%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brownsemi-solid. (TLC system: 5% MeOH in DCM R_(f): 0.22.).

Step 5: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to asolution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g,53.418 mmol) and 35 wt % aq. formaldehyde (45 mL, 0.534 mol) inacetonitrile (130 mL) at 0° C. The reaction mixture was warmed up toroom temperature and stirred for 16 h. The reaction mixture was quenchedwith sat. aq. NH₄Cl and concentrated under reduced pressure. The residuewas dissolved in water and extracted with EtOAc (3×200 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to afford 10.5 g (72%) of4-dimethylamino-4-pyridin-2-cyclohexan-1-one (INT-961) as a light brownsolid. (TLC system: 5% MeOH in DCM R_(f): 0.32.). [M+H]⁺ 219.1

Synthesis of INT-965: 4-Dimethylamino-4-phenyl-cyclohexan-1-one

Step 1: 8-(Dimethylamino)-1,4-dioxaspiro 4.5] decane-8-carbonitrile

Diethylamine hydrochloride (52 g, 0.645 mol) was added to the solutionof 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL)at RT wider argon atmosphere. The solution was stirred for 10 min and 40wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) weresequentially added. The reaction mixture was stirred for 48 h at RT,then diluted with water (100 mL) and extracted with EtOAc (2×200 mL).The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 44 g of8-(dimethylamino)-1,4-dioxaspiro-[4.5]decane-8-carbonitrile (93%) as awhite solid.

Step 2: N,N-dimethyl-8-phenyl-1,4-dioxaspiro [4.5] decan-8-amine

8-(Dimethylamino)-1,4-dioxaspiro[4.5]decan-8-carbonitrile (35 g, 0.167mol) in THF (350 mL) was added to the solution of 3M phenylmagnesiumbromide in diethyl ether (556 mL, 1.67 mol) dropwise at −10° C. underargon atmosphere. The reaction mixture was stirred for 4 h at −10° C. to0° C. and then at RT for 18 h. The reaction completion was monitored byTLC. The reaction mixture was cooled to 0° C., diluted with sat. aq.NH₄Cl (1 L) and extracted with EtOAc (2×600 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 60 g of, N N-dimethyl-8-phenyl-1,4-dioxaspiro-[4.5]-decan-8-amine as a liquid.

Step 3: 4-(dimethylamino)-4-phenylcyclohexanone

A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32g, 0.123 mol) in 6N aq. HCl (320 mL) was stirred at 0° C. for 2 h andthen at RT for 18 h. The reaction completion was monitored by TLC. Thereaction mixture was extracted with DCM (2×150 mL). The aqueous layerwas basified to pH 10 with solid NaOH and extracted with ethyl acetate(2×200 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The solid residue was washedwith hexane and dried in vacuo to afford 7 g of4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps)as a brown solid. [M+H]⁺ 218.1

Synthesis of INT-966:3-[(4-Methoyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione

KCN (93.8 g, 1441.6 mmol) and (NH₄)₂CO₃ (271.8 g, 1729.9 mmol) wereadded to the solution of 1,4-dioxaspiro[4.5]decan-8-one (150 g, 961mmol) in MeOH:H₂O (1:1 v/v) (1.92 L) at RT under argon atmosphere. Thereaction mixture was stirred at 60° C. for 16 h. The reaction completionwas monitored by TLC. The reaction mixture was cooled to 0° C., theprecipitated solid was filtered off and dried in vacuo to afford 120 g(55%) of9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione. Thefiltrate was extracted with DCM (2×1.5 L). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford additional 30 g (14%) of9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione (TLCsystem: 10% Methanol in DCM; Rf: 0.4).

Step 2:2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8.2}̂{5}]tetradecane-1,3-dione

Cs₂CO₃ (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g,663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reactionmixture was stirred for 30 min. A solution of p-methoxybenzyl bromide(96 mL, 663.4 mmol) was added. The reaction mixture was stirred at RTfor 48 h. The reaction completion was monitored by TLC. The reactionmixture was quenched with sat. aq. NH₄Cl (1.0 L) and the organic productwas extracted with EtOAc (2×1.5 L). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was washed with diethyl ether and pentane and dried underreduced pressure to afford 151 g (65%) of2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dioneas an off white solid (TLC system: 10% MeOH in DCM; Rf: 0.6).

Step 3:2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one

AlCl₃ (144.3 g, 1082.6 mmol) was added to a solution of LiAlH₄ (2M inTHF) (433 mL, 866.10 mmol) in THF (4.5 L) at 0° C. under argonatmosphere and the resulting mixture was stirred at RT for 1 h,2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione(150 g, 433.05 mmol) was added at 0° C. The reaction mixture was stirredat RT for 16 h. The reaction completion was monitored by TLC. Thereaction mixture was cooled to 0° C., quenched with sat. aq. NaHCO₃ (500mL) and filtered through celite pad. The filtrate was extracted withEtOAc (2×2.0 L). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford 120 g (84%) of2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-oneas an off-white solid. (TLC system: 10% MeOH in DCM, Rf: 0.5).

Step 4: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4,5]decane-2-dione

A solution of2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one (120 g, 361.03 mmol) in 6N aq. HCl (2.4 L) was stirredat 0° C. for 2 h and then at RT for 18 h. The reaction completion wasmonitored by TLC. The reaction mixture was extracted with DCM (2×2.0 L).The aqueous layer was basified to pH 10 with 50% aq. NaOH and thenextracted with DCM (2×2.0 L). Combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The solidresidue was washed with hexane and dried in vacuo to afford 90 g of3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione(INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.4)[M+H]⁺ 289.11.

Synthesis of INT-971:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1CIS-8-Dimethylamino-8-[3-(methoxymethoxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-968) was converted intoCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

TFA (0.2 mL) was added to the solution ofCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one(300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 3 h. The reaction completion was monitored by TLC.The reaction mixture was quenched with sat. aq. NaHCO₃ and the organicproduct was extracted with DCM (3×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purification of the residue by preparative TLC (3% MeOH in DCMas mobile phase) yielded 50 mg (18%) ofCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-971) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20)[M+H]⁺ 478.3

Synthesis of INT-974:CIS-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1:8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added to a solutionof 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione(INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argonatmosphere. The solution was stirred for 15 min and 40 wt % aq.dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentiallyadded. The reaction mixture was stirred for 48 h and the completion ofthe reaction was monitored by NMR. The reaction mixture was diluted withwater (1.0 L) and the organic product was extracted with ethyl acetate(2×2.0 L). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford 90 g (85%) of8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrileas an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf:0.35, 0.30).

Step 2:CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

3-Fluorophenylmagnesium bromide (1M in THF) (220 mL, 219.17 mmol) wasadded dropwise to a solution of8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(15 g, 43.83 mmol) in THE (300 mL) at 0° C. under argon atmosphere. Thereaction mixture was stirred for 16 h at RT. The reaction completion wasmonitored by TLC. The reaction mixture was cooled to 0° C., quenchedwith sat. aq. NH₄Cl (200 mL) and the organic product was extracted withEtOAc (2×200 mL). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The reaction was carriedout in 4 batches (15 g×2 and 5 g×2) and the batches were combined forpurification. Purification of the crude product by flash columnchromatography on silica gel (230-400 mesh) (2 times) (0-20% methanol inDCM) eluent and subsequently by washing with pentane yielded 5.6 g (11%)ofCIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-974) as an off-white solid. (TLC system: 5% MeOH in DCM in presenceof ammonia; Rf: 0.1). [M+H]⁺ 412.2

Synthesis of INT-975:CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution ofCIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reactionmixture was stirred for 30 min. 4-Methoxybenzyl bromide (4.23 mL, 29.30mmol) was added and stirring was continued at RT for 4 h. The reactioncompletion was monitored by TLC. The reaction mixture was diluted withsat. aq. NH₄Cl (150 mL) and the organic product was extracted with EtOAc(2×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated in vacuo. The reaction was carried out in 2 batches (8g×2) and the batches were combined for purification. Purification of thecrude product by flash column chromatography on silica gel (0-10%methanol in DCM) and subsequently by washing with pentane yielded 11 g(47%) ofCIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) as a white solid. [M+H]⁺ 394.2

Synthesis of INT-976:CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione

In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2g, 9.22 mmol) was suspended in 40 mL EtOH/H₂O (1:1 v/v) at RT underargon atmosphere. (NH₄)₂CO₃ (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22mmol) were added. The reaction mixture was stirred at 60° C. for 18 h.The reaction mixture was cooled to 0° C. and diluted with ice-water andfiltered through a glass filter. The solid residue was dried underreduced pressure to afford8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g,86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf:0.25).

Step 2: 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro [4, 5] decan-2-one

LiAlH₄ (2M in THF) (70 mL, 139.4 mmol) was added to the solution of8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (10 g,34.8 mmol) in THF/Et₂O (2:1 v/v) (400 mL) at 0° C. under argonatmosphere. The reaction mixture was stirred for 4 h at 60° C. Thereaction completion was monitored by TLC. The reaction mixture wascooled to 0° C., quenched with saturated Na₂SO₄ solution (100 mL) andfiltered through Celite pad. The filtrate was dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford 5.7 g (59%) of8-(dimethylamino)-8-phenyl-1, 3-diazaspiro [4, 5]decan-2-one as an offwhite solid. (TLC system: 10% MeOH in DCM, Rf: 0.3).

Step 3: CIS-8-Dimethylamino-1-phenyl-1,3-diazaspiro[4.5]decan-2-one

A mixture of CIS- andTRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8 g,29.30 mmol) was purified by preparative chiral SFC (column: ChiralcelAS-H, 60% CO₂, 40% (0.5% DEA in MeOH)) to get 5 g ofCIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) asa white solid. [M+H]⁺ 274.2.

Synthesis of INT-977:CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid; 2,2,2-trifluoro-acetic acid salt

Step 1:CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester

A solution ofCIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was cooledto 0° C. and treated with LDA solution (2M in THF/heptane/ether, 25.4mL, 50.8 mmol). The resulting mixture was was allowed to warm up to RTover 30 min. The solution was then cooled to 0° C. again andtert-butyl-bromoacetate (5.63 mL, 38.1 mmol) was added. The reactionmixture was stirred at RT for 16 h. quenched with water and extractedwith DCM (3×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. Purification of theresidue by column chromatography on silica gel providedCIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (4.4 g).

Step 2:cis-2-(8-Dimethylamino-2-oxo-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid trifluoroacetic acid salt

CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) andheated to reflux overnight. After cooling to RT all volatiles areremoved in vacuo. The residue was taken up in THF (1 mL) and addeddropwise to diethyl ether (20 mL). The resulting precipitate wasfiltered off and dried under reduced pressure to giveCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a whitesolid. [M+H]⁺ 332.2

Synthesis of INT-978:CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide

CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) wasdissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol),dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) weresequentially added. The reaction mixture was stirred at RT overnight,then diluted with 1 M aq. Na₂CO₃ (5 mL). The aqueous layer was extractedwith DCM (3×5 mL), the combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel to yieldCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide(INT-978) (39 mg) as a white solid. [M+H]⁺ 359.2

Synthesis of INT-982:CIS-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was stirred at RTfor 10 min.CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (7.00 g, 17.8 mmol) was added and stirring wascontinued for 15 min. 1-(Bromo-methyl)-1-methyl-cyclobutane (8.7 g, 53.4mmol) was added at 0° C. The reaction mixture was heated to 60° C. for16 h. After cooling down to RT, water (100 mL) was added and the mixturewas extracted with DCM (3×150 mL). The combined organic layers werewashed with water (70 mL), brine (100 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. Purification of the residue bycolumn chromatography on silica gel providedCIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(6.5 g) as a light yellow solid.

Step 2:CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To the solution ofCIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.66 g, 14.0 mmol) in DCM (65 mL) was added TFA (65mL) and the resulting mixture was stirred at RT for 16 h. The reactionmixture was concentrated under reduced pressure. The residue was takenup in DCM (100 mL) and water (60 mL) and basified with 2M aq. NaOH to pH10. The organic layer was separated and washed with brine (40 mL), driedover MgSO₄, filtered and concentrated under reduced pressure.Crystallization of the residue from EtOAc providedCIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-982) (3.41 g) as an off-white solid. [M+H]⁺ 356.3

Synthesis of INT-984:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) was converted intoCIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 2CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-onewas converted into CIS-1-(Cyclobutyl-metyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-984).

Synthesis of INT-986:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution ofCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. Thereaction mixture was basified with 2N aq. NaOH to pH-10 and the organicproduct was extracted with DCM (3×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas stirred vigorously with a mixture of 10 wt % aq. citric acid (5 mL)and DCM (10 mL) at RT for 10 min. The reaction mixture was basified with5N aq. NaOH to pH-10 and extracted with DCM (3×10 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuoto give 3.5 g (crude) ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneas semi solid (TLC system: 10% MeOH in DCM; R_(f): 0.60.).

Step 2:CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was added to thesolution ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78 mmol, 2 equiv.) andacetic acid (0.5 mL) in methanol (20 mL). The reaction mixture wasstirred at RT for 3 h. then quenched with sat. aq. NaHCO₃ and theorganic product was extracted with DCM (3×50 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded 2.3 g(62%) ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as a solid. (TLC system: 50% EtOAc in Pet. Ether,R_(f): 0.65).

Step 3:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-986)

Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia(0.25 mL) at −78° C. The resulting mixture was stirred for 10 min at−78° C. A solution ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(2.3 g, 5.16 mmol) in THF (25 mL) was added at −78° C. The reactionmixture was stirred for 15 min, then quenched with sat. aq. NH₄Cl,warmed to RT and stirred for 1 h. The organic product was extracted withDCM (3×50 mL). The combined organic layer was washed with water, brineand concentrated under reduced pressure to afford 1.30 g (72%) ofCIS-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-986) as an off-white solid. (TLC system: 100% MeOH in DCM R_(f):0.15.). [M+H]⁺ 356.3

Synthesis of INT-987:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method as described for INT-982 step 2CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-952) was converted intoCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-987).

Synthesis of INT-988:CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS4-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]4-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium hydroxide (78.06 mg, 4.0 equiv.) was suspended in DMSO (3.5 mL),stirred for 10 minutes,8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (192.0 mg, 1.0 equiv.) was added, the reaction mixture wasstirred for 5 min followed by addition of 2-(1-methoxycyclobutyl)ethyl4-methylbenzenesulfonate (416.2 mg, 3.0 equiv.) in DMSO (1.5 mL). Theresulting mixture was stirred overnight at 50° C. The reaction mixturewas quenched with water and extracted with DCM (3×20 mL). The combinedorganic phases were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue (283 mg yellow oil) waspurified by column chromatography on silica gel (eluent DCM/EtOH 98/2 to96/4) to give8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl)-3-(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one163 mg (66%).

Step 2:CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-988)

In analogy to the method described for INT-982 step 2CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-onewas converted intoCIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988). Mass: m/z 386.3 (M+H)⁺.

Synthesis of INT-989:CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)(1250 mg, 4.6 mmol), 5-bromo-2-chloro-pyrimidine (1.5 equiv., 6.7 mmol,1327 mg), Cs₂CO₃ (2 equiv., 9.15 mmol, 2980 mg). XantPhos (0.15 equiv.,0.69 mmol, 397 mg) and Pd₂(dba)₃ (0.05 equiv., 0.23 mmol, 209 mg) weredissolved in dry 1,4-dioxane (120 equiv., 549 mmol, 47 mL) undernitrogen atmosphere and stirred at 90° C. overnight. The reactionmixture was cooled down, diluted with water (50 mL), extracted with DCM(3×70 mL), the combined organic phases were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue (2.8 g) was suspendedin 10 mL DCM and stirred for 10 min. The resulting precipitate wasfiltered off and washed with small amount of DCM to give 1213 mg ofCIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-989) as a white solid. The mother liquor was concentrated underreduced pressure (1428 mg), suspended in 3 mL DCM, 3 mL pentane wereslowly added and the mixture was stirred for 30 min. The precipitate wasfiltered off, washed with small amounts of pentane and DCM to givesecond portion of INT-989 (215 mg) as a light yellow solid. ¹H NMR (600MHz, DMSO) δ 8.94 (s, 2H), 7.88 (s, 1H), 7.41-7.33 (m, 4H), 7.27 (tt,1H), 3.65 (s, 2H), 2.49-2.32 (m, 2H), 1.98-1.88 (m, 2H), 1.96 (s, 6H),1.87-1.73 (m, 2H), 1.53-1.47 (m, 2H). Mass: m/z 386.2 (M+H)⁺.

Synthesis of INT-991: lithiumCIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate

MethylCIS-5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carboxylate(INT-990) (950 mg, 2.32 mmol) was suspended in a mixture of MeOH (140equiv., 325 mmol, 13 mL) and THF (70 equiv., 162 mmol, 13 mL). Lithiumhydroxide 2M aq. sol. (1.3 mL) was added. The reaction mixture wasstirred 5 days at RT. Additional 1.3 mL of lithium hydroxide 2M aq. sol,were added and the reaction mixture was stirred for 2 h at RT. Thesolvents were removed under reduced pressure. The residue was suspendedin EtOAc (10 mL) and stirred overnight. The precipitate was filtered off(1.07 g) and washed with DCM (3 mL), pentane and dried under reducedpressure. The resulting solid (960 mg) containing INT-990 and residuallithium salts was used directly in the next steps. Mass: m/z 394.2(M-Li)⁻.

Synthesis of INT-1008:CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one

Step 1 and step 2: ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-aminehydrochloride (INT-1004)

A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0eq.) and 2M solution of EtNH₂ in THF (200 ml, 2.5 eq. 400.64 mmol) inEtOH (30 ml) was stirred at RT for 48 h. The reaction mixture wasconcentrated under argon atmosphere and the residue was diluted withether (60 ml), and a freshly prepared PhLi solution was added [preparedby addition of 2.5M n-BuLi in THF (70.5 ml, 1.1 eq. 176.27 mmol) to asolution of bromobenzene (27.675 g, 1.1 eq. 176.275 mmol) in ether (100ml) at −30 OC and stirred at RT for 1 h). The reaction mixture wasstirred at RT for 1.5 h, quenched with saturated NH₄Cl solution (100 ml)at 0° C. and extracted with ethyl acetate (2×750 ml). The combinedorganic layer was washed with water (3×350 ml), brine (300 ml), driedover Na₂SO₄ and concentrated under reduced pressure. The resultingresidue was dissolved in ethyl methyl ketone (100 ml) and trimethylsilylchloride (37.5 ml) was added at 0° C. The resulting mixture was stirredat RT for 16 h. The precipitated solid was filtered off and washed withacetone followed by THF to getethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride as anoff white solid. This reaction was done in 2 batches of 25 g scale andthe yield is given for 2 combined batches. Yield: 18% (17.1 g, 57.575mmol). LCMS: m/z 262.2 (M+H)⁺.

Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)

To a solution of ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-aminehydrochloride (10.1 g, 34.0 mmol, 1 eq.) in water (37.5 ml) was addedconc. aq. HCl (62.5 ml) at 0° C. and the resulting mixture was stirredat RT for 16 h. The reaction mixture was basified with aq. NaOH (pH˜14)at 0° C. and extracted with DCM (2×750 ml). Organic layer was washedwith water (400 ml), brine (400 ml), dried over Na₂SO₄ and concentratedunder reduced pressure to yield 4-ethylamino-4-phenyl-cyclohexanonewhich was used in the next step without further purification. Thisreaction was carried out in another batch of 15.1 g scale and the yieldis given for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).

Step 4: cis and trans mixture of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006 andINT-1007)

To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g, 78.341 mmol,1.0 eq.) in EtOH (250 ml) and water (200 ml) was added (NH₄)₂CO₃ (18.8g, 195.85 mmol, 2.5 eq.) and the reaction mixture was stirred at RT for15 min. KCN (5.09 g, 78.341 mmol, 1.0 eq.) was added and stirring wascontinued at 60° C. for 18 h. The reaction mixture was cooled down toRT. The precipitated solid was filtered off, washed with water (250 ml).EtOH (300 ml), hexane (200 ml) and dried under reduced pressure to yieldcis and trans mixture of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g,45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296 mmol).LC-MS: m/z [M+1]⁺=288.2.

Step 5: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione(INT-1006)

To a solution of cis and trans mixture of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g) inMcOH-DCM (1:1, 960 ml) was added a solution of L-tartaric acid in MeOH(25 ml) and the resulting mixture stirred at RT for 2 h and then kept inrefrigerator for 16 h. The precipitated solid was filtered off andwashed with MeOH-DCM (1:5, 50 ml) to get tartrate salt of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (7.5 g) as awhite solid. To this solid sat. aq. NaHCO₃ was added (pH-8) and theresulting mixture was extracted with 25% MeOH-DCM (2×800 ml). Combinedorganic layer was washed with water (300 ml), brine (300 ml), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas triturated with 20% DCM-hexane and the resulting solid was driedunder reduced pressure to affordCIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as whitesolid. This step was done in 2 batches (12 g & 2.4 g) and the yield isgiven for 2 combined batches. Yield: 31.2% (5.0 g, 17.421 mmol). LC-MS:m/z [M+1]⁺=288.0.

Step 6: CIS4-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(INT-1008)

To a slurry of LiAlH₄ (793 mg, 20.91 mmol, 3.0 eq.) in THE (15 ml) wasadded a suspension ofCIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0 g,6.97 mmol, 1.0 eq.) in THF (60 ml) at 0° C. and the reaction mixture washeated to 65° C. for 16 h. The reaction mixture was cooled to 0° C.,quenched with sat. aq. Na₂SO₄ (20 ml), stirred at RT for 1 h andfiltered through celite pad. The residue was washed with 15% MeOH-DCM(500 mil). The combined filtrate was dried over anhdrous Na₂SO₄ andconcentrated under reduced pressure to give crude product which wastriturated with 15% DCM-Hexane to affordCIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)(1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84% (1.6 g, 5.86 mmol).LC-MS: m/z [M+1]⁺=274.2.

Synthesis of INT-1026:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide

Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) atRT and the reaction mixture was stirred at RT for 18 h. The reactionmixture was cooled to 0° C. and quenched by dropwise addition of sat.aq. NaHCO₃ (500 mL) over a period of 30 min. The organic product wasextracted with EtOAc (3×100 mL). The combined organic extracts weredried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 10 g(crude) of2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide asa white solid (TLC system: 30% Ethyl acetate in hexane; Rf: 0.30).

Step 2:2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide

Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwiseto a solution of2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10g, 38.61 mmol) in THF (500 mL) at −10° C. under argon atmosphere. Thereaction mixture was stirred for 2 h at −10° C. to 0° C. The reactioncompletion was monitored by TLC. The reaction mixture was quenched withsat. aq. NH₄Cl (50 mL) at 0° C. and the organic product was extractedwith EtOAc (3×100 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel 230-400 mesh; 40-60% ethyl acetate inhexane) to yield 6.0 g (46%) of2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamideas a liquid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.30).

Step 3: 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride

2N solution of HCl in diethyl ether (17.80 mL, 35.60 mmol) was added toa solution of2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide(6.0 g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture wasstirred at RT for 2 h. The reaction mixture was concentrated in vacuo.The residue was washed with diethyl ether to yield 3 g (crude) of8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid(TLC system: 5% MeOH in DCM; Rf: 0.10).

Step 4:8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine

Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a solution of8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (3.0 g, 11.15mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL, 22.30 mmol) andacetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixturewas stirred at RT for 16 h. The reaction mixture was concentrated invacuo at 30° C. and to the residue sat. aq. NaHCO₃ was added. Theorganic product was extracted with DCM (3×30 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and solvent was concentratedunder reduced pressure to get 3 g (crude) of8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amineas a semi-solid (TLC system: 10% McOH in DCM; Rf: 0.22).

Step 5:N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)

Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a solution of8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine(3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60 mmol) andacetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixturewas stirred at RT for 16 h. The reaction mixture was concentrated invacuo and to the residue sat. aq. NaHCO₃ was added. The organic productwas extracted with DCM (3×30 mL). The combined organic extracts weredried over anhydrous Na₂SO₄ and solvent was concentrated under reducedpressure. The resulting residue was purified by column chromatography(silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 2.50 g (83%) ofN-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amineas a semi solid (TLC system: 10% MeOH in DCM; Rf: 0.25).

Step 6:4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone

5% sulfuric acid in water (25 mL) was added toN-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine(2.50 g, 7.55 mmol) at 0° C. and the resulting mixture was stirred at RTfor 24 h. The reaction mixture was quenched with sat. aq. NaHCO₃ and theorganic product was extracted with DCM (2×50 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated in vacuo toafford 2.0 g (crude) of4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone as athick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).

Step 7:8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone(1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H₂O (1:1 v/v) at RTunder argon atmosphere. (NH₄)₂CO₃ (1.9 g, 13.05 mmol) and KCN (0.34 g,5.22 mmol) were added. The reaction mixture was heated to 70° C. for 16h. The reaction mixture was diluted with ice-water and the organicproduct was extracted with DCM (2×50 mL). The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated in vacuo to give 1.0 g(crude) of8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2,4-dioneas a solid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.18).

Step 8:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

Diastereomeric mixture of8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione(1.0 g) was separated by reverse phase preparative HPLC to afford 400 mgof isomer 1(CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione)and 60 mg of isomer 2(TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione)and 300 mg of mixture of both isomers. Reverse phase preparative HPLCconditions: mobile phase: 10 mM ammonium bicarbonate inH₂O/acetonitrile, column: X-BRIDGE-C18 (150*30), 5 μm, gradient (T/B %):0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min,diluent: mobile phase+THF.

Step 9:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1026)

LiAlH₄ (1M in THF) (4.48 mL, 4.48 mmol) was added to a solution ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione(isomer-1) (0.4 g, 1.12 mmol) in THF:Et₂O (2:1 v/v, 15 mL) at 0° C.under argon atmosphere. The reaction mixture was stirred at 65° C. for16 h. The mixture was cooled to 0° C., quenched with sat. aq. Na₂SO₄(1000 mL) and filtered through celite pad. The filtrate was dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) toyield 0.3 g (78%) ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1026) as an off white solid. (TLC system: 10% MeOH in DCM, Rf:0.2). LC-MS: m/z [M+1]⁺=344.2.

Synthesis of INT-1031:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-952CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-974) was converted intoCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-(3-fluorphenyl)-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 21-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methl]-1,3-diazaspiro[4.5]decan-2-one was converted into1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1031).

Synthesis of INT-1037:8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one

Lithiumaluminumhydride (2.2 equiv., 292 mmol) was suspended in THF (400mL) and the suspension was cooled to 0° C.8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg,0,261 mmol) (step 1 of INT-965) was added portionwise at 0° C. Thereaction mixture was stirred 1.5 h at 0° C., then overnight at RT andthen 2 h at 40° C. The reaction mixture was cooled down to 0° C.,quenched carefully with sat. aq. Na₂SO₄, EtOAc (400 mL) was added andthe resulting mixture was stirred for 2 h and then left without stirringfor 2 h at RT. The precipitate was filtered off and washed with EtOAcand MeOH. The resulting solid residue was suspended in methanol andstirred at RT overnight. The precipitate was filtered off and disposed.The filtrate was concentrated under reduced pressure, the residue wassuspended thoroughly in water (50 mL) at 40° C., the precipitate wasfiltered off and dried under reduced pressure to yield9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one (11.4 g,41%). Mass: m/z 213.2 (M+H)⁺.

Step 2: 1,3-diazaspiro[4.5]decane-2,8-dione

In analogy to the method described for INT-1003 step 39,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one was treatedwith conc. aq. HCl to be converted into1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1 (M+H)⁺.

Step 3: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(INT-1037)

In analogy to the method described for INT-965 step 11,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine andpotassium cyanide to be converted into8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(INT-1037). Mass: m/z 223.2 (M+H)⁺.

Synthesis of INT-1038:CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one

To the suspension of8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (200mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise 1Mbromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and thereaction mixture was stirred for 1 h at RT. Additional portion of 1Mbromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. Thereaction mixture was stirred at RT overnight, then quenched withmethanol/water. Solid NH₄Cl and DCM were added to the resulting mixtureand the precipitate was filtered off. The organic phase of the filtratewas separated and the aqueous phase was extracted with DCM (3×). Thecombined organic phases were dried over anhydr. Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (DCM/MeOH, 100/0 to 65/35) to yieldCIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H)⁺.

Synthesis of INT-1059:TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (250.0g, 1.15 mol, 1.0 eq.) in EtOH (2.5 L) and water (2.1 L) was added(NH)₂CO₃ (276.2 g, 2.87 mol, 2.5 eq.) and the reaction mixture wasstirred at RT for 15 min. KCN (74.92 g, 1.15 mol, 1.0 eq.) was added.The reaction mixture was stirred at 60° C. for 18 h and then filtered inhot condition to get white solid which was washed with water (2.5 L),ethanol (1 L) and hexane (2.5 L). The resulting solid was dried underreduced pressure to getCIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223g, 0.776 mol, 65%) as a white solid. The filtrate was collected frommultiple batches (˜450 g) which contained a mixture of cis and transisomers. The filtrate was concentrated under reduced pressure and solidobtained was filtered and washed with water (1 L) and hexane (1 L).Solid material was dried under reduced pressure to get ˜100 g of amixture of cis and trans (major) isomers. Crude material was partiallydissolved in hot MeOH (600 mL) and cooled to RT, filtered throughsintered funnel washed with MeOH (200 mL) followed by ether (150 mL) anddried to getTRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (50g, 0.174 mmol, ˜9-10%).

Step 2: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1059)

In analogy to the method described for INT-976 step 2TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione wastreated with LiAlH₄ to be converted intoTRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1059). Mass: m/z 274.2 (M+H)⁺.

Synthesis of INT-1068 and INT-1069: CIS- andTRANS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g,230.096 mmol) in MeOH (400 mL) was added NH₄Cl (24.6 g, 460.8 mmol)followed by NH₄OH (400 mL) at RT and the reaction mixture was stirredfor 15 min. NaCN (22.5 g, 460.83 mmol) was added and the resultingmixture was stirred for 16 h at RT. The reaction mixture was extractedwith DCM (3×750 mL). Combined organic layer was washed with water (750mL), brine (750 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was triturated with DCM/hexane to get crude1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) asan off white solid which was used in next step without furtherpurification. LC-MS: m/z [M+H]⁺=244.2 (MW calc. 244.09).

Step 2:N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide

To a solution of1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g, 20.57mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml, 61.71 mmol,3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2 eq) and T3P(18.2 ml, 30.85 mmol, 1.5 eq) at 0° C. The reaction mixture was stirredat RT for 16 h. then diluted with water (100 ml) and extracted with 10%MeOH in DCM (2×250 mL). Combined organic layer was washed with brine(100 mL), dried over Na₂SO₄ and concentrated under reduced pressure toget crudeN-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl-cyclohexyl)-2,2,2-trifluoroacetamideas a light yellow sticky material which was used in the next stepwithout further purification. LC-MS: m/z [M+1]=339.9 (MW calc. 339.36).

Step 3:1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

To suspension of LiAlH₄ (4.03 g, 106.19 mmol, 6.0 eq.) in dry THF (40mL) was addedN-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide(6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at 0° C. Thereaction mixture was stirred at RT for 16 h, then quenched with sat. aq.Na₂SO₄ at 0° C. excess THF was added and the resulting mixture wasstirred at RT for 2 k. The resulting suspension was filtered throughcelite and the filter cake was washed with 10% MeOH in DCM (150 mL).Combined filtrate was concentrated under reduced pressure to yield crude1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine(4.2 g, crude) as a light yellow sticky material which was directly usedin the next step without further purification. LC-MS: m/z [M+1]⁺=330.0(MW calc. 329.40).

Step 4: CIS- andTRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1068 and INT-1069)

To a solution of1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine(4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was added KOH (4.29 g,76.56 mmol, 6.0 eq.) in water (120 ml) at 0° C. followed by addition ofCOCl₂ (15.6 ml, 44.66 mmol, 3.5 eq., 20% in toluene) at 0° C. andstirred at RT for 16 h. Reaction mixture was basified with sat NaHCO₃solution and extracted with DCM (2×200 ml). Combined organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to get crudeproduct which was purified by prep HPLC to getCIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1068) (1.5 g) (major isomer, polar spot on TLC) andTRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% byHPLC) as off-white solids. CIS-isomer LC-MS: m/z [M+1]⁺=356.2 (MWcalc.=355.40). HPLC: 98.53%. Column: Xbridge C-18 (100×4.6), 5μ,Diluent: MeOH. Mobile phase: A) 0.05% TFA in water. B) ACN flow rate: 1ml/min, R_(f)=5.17 min. ¹HNMR (DMSO-d₆, 400 MHz), δ (ppm)=7.43-7.27 (m,5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J=12.72 Hz),1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23 (m, 2H).

For further intermediates the synthesis in analogy to previouslydescribed methods is given in the following table. The syntheses of thebuilding blocks and intermediates have either been described previouslywithin this application or can be performed in analogy to the hereindescribed methods or by methods known to the person, skilled in the art.Such a person will also know which building blocks and intermediatesneed to be chosen for synthesis of each exemplary compound.

Inter- in analogy to m/z mediate Chemical Name Chemical Structure method[M + H]⁺ INT-601 CIS-5-(-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro [4.5]decan-3-yl)pyrimidine-2-carbonitrile

INT-600 395.1 INT-794 CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one

INT-975 424.3 INT-796 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3- methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-one

INT-974 390.3 INT-797 CIS-8-(Ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5] decan-2-one

INT-976 288.2 INT-949 CIS-8-Dimethylamino-1-ethyl-8-phenyl-1,3-diazaspiro[4.5] decan-2-one

INT-984 302.2 INT-950 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- [phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one

INT-952 432.3 INT-954 4-Dimethylamino-4-(5-methyl-thiophen-2-yl)-cyclohexan-1-one

INT-965 238.1 INT-955 4-Dimethylamino-4-thiophen-2-yl- cyclohexan-1-one

INT-965 224.1 INT-956 1-(1-Methyl-1H-pyrazol-3-yl)-4-oxo-cyclohexane-1-carbonitrile

INT-958 204.1 INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1-carbonitrile

INT-958 202.1 INT-959 4-Dimethylamino-4-(1-methyl-1H-pyrazol-3-yl)-cyclohexan-1-one

INT-961 222.2 INT-960 4-Dimethylamino-4-pyrazin-2-yl- cyclohexan-1-one

INT-961 220.1 INT-962 4-Dimethylamino-4-(3-methoxyphenyl)-cyclohexan-1-one

INT-965 248.2 INT-963 CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2- one

INT-975 364.2 INT-964 4-(Ethylmethyl-amino)-4-phenyl- cyclohexan-1-one

INT-965 232.2 INT-967 CIS-8-Dimethylamino-8-[4-(methoxymethyloxy)-phenyl]-3- [(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

INT-974 454.3 INT-968 CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3- [(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

INT-974 454.3 INT-969 CIS-1 -(Cyclobutyl-methyl)-8- dimethylamino-8-(4-hydroxyphenyl)-3-[(4- methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

INT-971 478.3 INT-970 CIS-8-Dimethylamino-8-(4- methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one

SC_2017 424.3 INT-972 CIS-8-Dimethylamino-8-(3- methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one

SC_2017 424.3 INT-973 CIS-8-Dimethylamino-8-(4- fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one

INT-974 412.2 INT-979 CIS-8-Dimethylamino-1-(3-methoxy-propyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one

INT-984 346.2 INT-980 CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one

INT-984 332.2 INT-981 CIS-8-Dimethylamino-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan- 2-one

INT-984 316.2 INT-983 CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one

INF-984 328.2 INT-985 CIS-1-(Cyclobutyl-methyl)-8-(methyl-propyl-amino)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one

INT-986 370.3 INT-990 methyl CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4,5] decan-3-yl)pyrimidine-2-carboxylate

INT-989 410.2 INT-992 CIS-3-(2-chloro-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-phenyl- 1,3-diazaspiro[4,5]decan-2-one

INT-989 400.2 INT-993 4-benzyl-4-(dimethylamino) cyclohexanone

INT-965 232.3 INT-994 CIS-8-benzyl-8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one

INT-976 288.2 INT-995 TRANS-8-benzyl-8- (dimethylamino)-1,3-diazaspiro[4.5]decan-2-one

INT-976 288.2 INT-997 CIS-8-(dimethylamino)-8-(thiophen-2-yl)-1,3-diazaspire[4.5] decan-2-one

INT-976 280.1 INT-998 TRANS-8-(dimethylamino)-8-(thiophen-2-yl)-1,3-diazaspiro[4.5] decan-2-one

INT-976 280.1 INT-999 4-(dimethylamino)-4-(1-methyl-1H-benzo[d]imidazol-2-yl) cyclohexanone

INT-965 272.2 INT-1000 CIS-8-(dimethylamino)-8-(1-methyl-1H-benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5]decan-2-one

INT-976 328.2 INT-1001 TRANS-8-(dimethylamino)-8-(1-methyl-1H-benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5]decan-2-one

INT-976 328.2 INT-1002 CIS-3-(2-chloropyrimidin-4-yl)-8-(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one

INT-989 386.9 INT-1009 TRANS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one

INT-1008 274.2 INT-1024 CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5] decan-2-one

INT-977 (step 2) 292.2 INT-1025 CIS-8-(dimethylamino)-8-(4-fluorophenyl)-1,3-diazaspiro[4.5] decan-2-one

INT-974, INT-977 (step 2) 292.2 INT-1027CIS-3-(2-chloropyrimidin-5-yl)-8- (dimethylamino)-8-(thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one

INT-989 392.1 INT-1039 CIS-8-(dimethylamino)-8-(3-(trifluoromethoxy)phenyl)-1,3- diazaspiro[4.56]decan-2-one

INT-1038 358.2 INT-1040 (CIS)-8-(dimethylamino)-8-(3-(trifluoromethyl)phenyl)-1,3- diazaspiro[4.5]decan-2-one

INT-1038 342.2 INT-1041 (CIS)-8-(dimethylamino)-8-(3-methoxyphenyl)-1,3-diazaspiro [4.5]decan-2-one

INT-1038 304.2 INT-1042 (CIS)-8-(5-chlorothiophen-2-yl)-8-(dimethylamino)-1,3-diazaspiro [4.5]decan-2-one

INT-1038 314.1 INT-1043 (CIS)-8-(dimethylamino)-8-(3-fluoro-5-methylphenyl)-1,3-diazaspiro [4.5]decan-2-one

INT-1038 306.2 INT-1044 (CIS)-8-(3-chlorophenyl)-8-(dimethylamino)-1,3-diazaspiro [4.5]decan-2-one

INT-1038 308.2 INT-1045 (CIS)-3-(5-chloro-3-fluoropyridin-2-yl)-8-(dimethylamino)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one

INT-989 403.2 INT-1047 (CIS)-8-(methyl(oxetan-3-ylmethyl)amino)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-1026 330.5 INT-1048 (CIS)-3-(6-chloropyridin-3-yl)-8-(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one

INT-989 385.2 INT-1049 (CIS)-3-(5-chloropyridin-2-yl)-8-(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one

INT-989 385.2 INT-1061 TRANS-1-(cyclopropyl-methyl)-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one

INT-984 328.2 INT-1063 CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3-diazaspiro[4.5] decan-2-one

INT-1031 346.2 INT-1066 TRANS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one

INT-987 342.3 INT-1070 CIS-8-(dimethylamino)-8-phenyl-1-(3,3,3-trifluoropropyl)-1,3- diazaspiro[4.5]decan-2-one

INT-1068 360.2 INT-1074 CIS-8-(dimethylamino)-8-(3- fluorophenyl)-1-((1-hydroxycyclobutyl)methyl)-1,3- diazaspiro[4.5]decan-2-one

INT-1031 376.2 INT-1076 CIS-3-(2-chloro-4 -methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

INT-989 418.2 INT-1077 CIS-3-(4-chloro-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)- 8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

INT-989 472.2 INT-1078 CIS-3-(4-chloro-2- cyclopropylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)- 1,3-diazaspiro[4.5]decan-2-one

INT-989 444.2

Synthesis of Exemplary Compounds

Synthesis of SC_3013:cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile

NaH (60% in mineral oil, 0.076 g, 3.19 mmol, 3 equiv.) was added to asolution of5-(cis-8-(dimethylamino)-2-oxo-phenyl-1,3-diazaspiro[4.5]decan-3-yl)perimidine-2-carbonitrileINT_600 (0.4 g, 1.06 mmol) in DMF (5 mL) at 0° C. The mixture wasstirred for 30 min at RT and then cooled to 0° C.(1-(Tert-butyldimethylsilyloxy)cyclobutyl)methyl4-methylbenzene-sulfonate (1.18 g, 3.19 mmol, 3 equiv.) was addeddropwise over a period of 5 min and the reaction mixture was allowed towarm up to RT and further heated to 70° C. for 16 h. The reactionmixture was diluted with water (10 mL) and extracted with EtOAc (3×20mL). The combined organic layers were dried over anhydrous Na₂SO₄ andthe solvent was removed in vacuo. The residue was purified by silica gelflash chromatography to affordCIS-5-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile(0.25 g).

Synthesis of SC_3014:cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile

cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneINT-987 (500 mg, 1.464 mmol), 2-chloropyrimidine-5-carbonitrile (409 mg,2.928 mmol) and Cs₂CO₃ (954 mg, 2.928 mmol) in 1,4-dioxane (6 ml) werestirred under an nitrogen atmosphere for 18 h at 105° C. The reactionmixture was cooled to RT, 2N aqueous NaOH solution (3 ml) was added andstirring was continued for 10 min. The mixture was extracted first withEtOAc and then with a blend of DCM (30 ml) and methanol (5 ml). Theorganic layers were combined and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel (elutionwith a DCM/EtOAc gradient) providedcis-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrileSC_3014 (57 mg).

Synthesis of SC_3016:cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylicacid amide

cis-2-[1-(Cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-5-carbonitrileSC_3014 (40 mg, 0.09 mmol) was dissolved in DMSO (1.2 mL) and K₂CO₃ (25mg, 0.18 mmol) and hydrogen peroxide (30%, 0.13 mL 1.260 mmol) wereadded. The reaction mixture was stirred at RT for 20 h, then dilutedwith 2N NaOH (10 mL) and extracted with DCM (3×20 mL). The combinedorganic layers were dried over Na₂SO₄, concentrated in vacuo. Theresidue was purified by flash chromatography to yieldcis-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylicacid amide SC_3016 (40 mg) as a white solid.

Synthesis of SC_3022:cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one

cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneINT-987 (240 mg, 0.7 mmol), Pd-XPhos Generation 2 (138 mg, 0.17 mmol),Cs₂CO₃ (457 mg, 1.4 mmol) and 5-bromo-2-(trifluoromethyl)pyrimidine (319mg, 1.4 mmol) were suspended in anhydrous 1,4-dioxane (3 mL) undernitrogen atmosphere and the resulting mixture was stirred at 100° C.overnight. The reaction mixture was cooled to RT and water (3 mL) wasadded. The aqueous layer was extracted with DCM (3×10 mL), the combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel to yield thetitle compound. Final purification using a strong cation exchange resingavecis-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-oneSC_3022 (145 mg) as a white solid.

Synthesis of SC_3028:cis-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide

Step 1: Lithium4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate

Methyl4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate SC_3081 (400 mg) was dissolved in methanol (5mL) and DCM (5 mL). Lithium hydroxide solution (2 M in water, 1 mL) wasadded and the resulting mixture was stirred overnight at RT. Allvolatiles were removed in vacuo to yield lithium4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate(403 mg).

Step 2cis-4[l-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide (SC_3028)

Lithium4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate (80 mg, 0.17 mmol) was suspended in DCM (1 mL)and triethylamine (0.23 mL, 1.7 mmol) and dimethylamine (2M solution inTHF, 0.17 mL) and T3P (0.20 mL, 0.34 mmol) were sequentially added. Theresulting mixture was stirred for 18 h at RT. Water (10 mL) was addedand the mixture was extracted with DCM (3×20 mL). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo and the residue waspurified by flash chromatography to yieldcis-4-[I-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamideSC_3028 (28 mg) as white solid.

Synthesis of SC_3045:cis-4-Methoxy-5-[1-(3-methoxypropyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile

N-iodosuccinimide (150 &g, 0.67 mmol) was added to a suspension ofcis-5-[8-(dimethylamino)-1-(3-methoxypropyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrileSC_3040 (214 mg, 0.44 mmol) in acetonitrile/THF (211 v/v, 10 mL) at RTand the resulting mixture was stirred for 16 h at RT. The reactionmixture was basified with 2N NaOH solution to pH-10 and the organicproduct was extracted with DCM (10 mL×3). The combined organic extractswere dried over anhydrous Na₂SO₄, the solvent was removed in vacuo andthe residue was purified by preparative flash chromatography to givecis-4-methoxy-5-[1-(3-methoxypropyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrileSC_3045 (81 mg) as a solid.

Synthesis of SC_3064:cis-2-[3-(2-cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide

Sodium hydroxide (51 mg, 1.3 mmol) was added to anhydrous DMSO (4.5 mL)and stirred for 10 minutes at room temperature.cis-5-[8-(Dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrileINT_600 (80 mg, 0.21 mmol) was added and the resulting mixture wasstirred at room temperature for 5 min and then heated to 50° C.2-Bromo-N-propyl-acetamide (153 mg, 0.85 mmol) was added and stirringwas continued at 50° C. for one hour. The reaction mixture was quenchedwith water (25 mL) and extracted with ethyl acetate (2×10 mL). Thecombined organic layers were washed with water (5 mL) and brine (5 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel to yieldcis-2-[3-(2-cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamideSC_3064 (22 mg) as a solid.

Synthesis of SC_3065:5-(cis-1-(Cyclobutylmethyl)-8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxypyrimidine-2-carbonitrile

Cs₂CO₃ (274 mg, 0.84 mmol) was added to the solution ofcis-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneINT_986 (150 mg, 0.42 mmol), Xanthphos (36 mg, 0.063 mmol), Pd₂(dba)₃(19 mg, 0.0211 mmol) and 5-bromo-4-methoxypyrimidine-2-carbonitrile (135mg, 0.633 mmol) in 1,4-dioxane (10 mL) under argon atmosphere. Themixture was flushed again with argon for 5 min and the reaction mixturewas stirred at 90° C. for 5 h. The reaction mixture was cooled to roomtemperature. The residue was diluted with water (20 mL) and the organicproduct was extracted with ethyl acetate (3×10 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and the solvent wasconcentrated under reduced pressure. The residue was purified bypreparative TLC (EtOAc/petroleum ether 1/9) to afford a white solid(0.15 g), which was further washed with n-pentane to give 0.1 g of5-(cis-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-diethoxypyrimidine-2-carbonitrileSC 3065.

Synthesis of SC_3008:cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile

cis-2-[1-(Cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfanyl-benzonitrile(320 mg, 0.66 mmol, prepared from 2-iodo-5-(methylthio)benzonitrile andINT-987 analogously to SC_3022) was dissolved in a mixture of methanol(9 mL) and water (8 mL). Oxone® (807 mg, 1.3 mmol) was added at RT andthe resulting mixture was stirred at RT for 18 h. Water (10 mL) wasadded and the mixture was extracted with DCM (3×20 mL). The combinedorganic layers were dried over Na₂SO₄, concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel to yieldcis-2-[1-(cyclobutylmethyl)-8-(dimethylimino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrileSC_3008 (66 mg) as a white solid.

Synthesis of SC_3023:cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Boron tribromide (1M in DCM, 0.38 mL, 0.387 mmol) was added to thesolution ofcis-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin-8-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3015 (180 mg, 0.387 mmol) in DCM (2 mL) at 0° C. The reaction mixturewas stirred for 30 min at 0° C. and then for 16 h at room temperature,quenched with methanol (2 mL), the solvents were removed under reducedpressure and the residue was purified by normal phase preparative HPLCto yieldcis-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3023 (60 mg, 34%) as a white solid. ¹H NMR (400) MHz, DMSO-d6, δ inppm): δ 8.43 (s, 2H), 7.35-7.25 (m, 5H), 5.50 (s, 1H), 3.67 (s, 2H),3.19 (s, 2H), 2.69-2.65 (m, 2H), 2.19-2.10 (m, 4H), 1.98-1.85 (m, 8H),1.68-1.61 (m, 1H), 1.51-1.39 (m, 5H).

Synthesis of SC_3025:cis-S-[8-Dimethylamino-1-2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile

Step 1:5-(cis-1-(2-(tert-Butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile

NaH (60% in mineral oil, 63.8 mg, 1.59 mmol) was added at 0° C. to thesolution of5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrileINT-600 (0.2 g, 0.53 mmol) in DMF (8 mL) for 10 min at 0° C. Thereaction mixture was stirred at RT for 30 min.(3-bromopropoxy)(tert-butyl)dimethylsilane (252 mg, 1.06 mmol) was addeddropwise over 5 min at 0° C. and the mixture was stirred for further 16h at RT. The reaction mixture was diluted with water (15 mL) andextracted with diethyl ether (3×25 mL). The combined organic extractswere dried over anhydrous Na₂SO₄, the solvents were removed underreduced pressure and the residue was purified by flash chromatography onsilica gel to afford5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile(100 mg, 34%) as a white solid.

Step 2:cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4]decan-3-yl]-pyrimidine-2-carbonitrile(SC_3025)

1M TBAF solution in THF (0.36 mL, 0.36 mmol) was added to5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile(0.1 g, 0.18 mmol) in THF (5 mL) at 0° C. The reaction mixture wasstirred at RT for 30 min, diluted with water (10 mL) and extracted withdiethyl ether (3×25 mL). The combined organic extracts were washed withsat. aq. NaHCO₃, water and brine and dried over anhydrous Na₂SO₄. Thesolvents were evaporated under reduced pressure and the residue waspurified by preparative TLC (ethyl acetate/n-hexane=45:55) and thenwashed with n-pentane (5 mL) to give ofcis-5-[8-dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile(70 mg, 80%) as a white solid. ¹H NMR (400 MHz, DMSO-d6, δ in ppm): δ9.18 (s, 2H), 7.38-7.26 (m, 5H), 4.84 (t, 1H), 3.82 (s, 2H), 3.55-3.51(m, 2H), 3.26-3.20 (m, 2H), 2.73-2.70 (m, 2H), 2.17-2.11 (m, 2H), 2.00(s, 6H), 1.57-1.43 (m, 4H).

Synthesis of SC_3097:CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

-   -   starting from here until the end of the section all procedures        were added

Step 1: 4-(5-bromopyrimidin-2-yl)morpholine

K₂CO₃ (14.2 g, 103 mmol) was added to the solution of morpholine (9.0 g,103 mmol) in acetonitrile (900 mL) and the resulting suspension wasstirred at RT for 1 h, 5-Bromo-2-chloropyrimidine (20 g, 103 mmol) wasadded portionwise. The reaction mixture was stirred for 16 h at 80° C.,then cooled down to RT and diluted with EtOAc (100 mL) and water (50mL). The organic product was extracted with EtOAc (2×100 mL). Thecombined organic layer was washed with brine (100 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel (100-200)mesh) (20% EtOAc in petroleum ether) to afford 18.0 g (71%) of4-(5-bromopyrimidin-2-yl)morpholine as an off white solid (TLC system:30% EtOAc in pet ether, Rf: 0.6).

Step 2:CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3097)

K₂CO₃ (0.53 g, 3.85 mmol, 2.5 equiv.) was added to the suspension ofCIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-799) (0.55 g, 1.54 mmol, 1 equiv.) and4-(5-bromopyrimidin-2-yl)morpholine (0.37 g, 1.54 mmol, 1 equiv.) indioxane (20 mL) and the resulting suspension was purged with nitrogenfor 5 min. Copper(I) iodide (0.29 g, 1.54 mmol, 1 equiv.) andtrans-1,2-diaminocyclohexane (0.35 g, 3.085 mmol, 2 equiv.) weresequentially added, the reaction vessel was sealed and the reactionmixture was stirred at 130° C. for 4 h. The reaction mixture was cooleddown to RT and diluted with EtOAc (20 mL) and aq. ammonia (10 mL). Theorganic product was extracted with EtOAc (2×50 mL). The combined organiclayer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. Purification of the resultingresidue by column chromatography on silica gel (100-200 mesh) (60-70%EtOAc in petroleum ether) afforded 0.35 g (48%) ofCIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3097) as an off white solid (TLC system: EtOAc, Rf: 0.7). ¹H NMR(DMSO-d6): δ 8.60 (s, 2H), 7.36-7.35 (m, 4H), 7.27-7.24 (m, 1H), 5.50(s, 1H), 3.72 (s, 2H), 3.62-3.61 (m, 8H), 3.21 (s, 2H), 2.70-2.66 (m,2H), 2.19-2.11 (m, 4H), 1.98 (s, 6H), 1.93-1.85 (m, 2H), 1.66-1.64 (m,1H), 1.53-1.42 (m, 5H). Mass: m/z 521.3 (M+H)⁺.

Synthesis of SC_3099:CIS-1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (162 mg, 0.72 mmol) was added to the solutionCIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morpholinopyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC-3097) (250 mg, 0.48 mmol) in acetonitrile (8.0 mL) and THF (8.0 mL)at 0° C. and the resulting mixture was stirred for 16 h at RT. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in EtOAc (2×30 mL), the organic layer was washed with 2Naq. NaOH solution, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by reverse phase prep. HPLCto yield 0.12 g (49%) ofCIS-1-((1-hydroxycyclobutyl)methyl)-8-methylamino)-3-(2-morpholinopyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3099) as an off white solid (TLC system 5% MeOH in DCM Rf: 0.5.).Preparative reverse phase HPLC conditions: column: Luna-Phenyl-Hexyl-C18(150*19 mm) 5 μm; mobile phase: 10 mM ammonium bicarbonate/acetonitrile,gradient (T/% B): 0/50, 7/85, 7.1/98, 9/98, 9.1/50, 12/50, flow Rate: 25ml/min diluent: mobile phase+THF. ¹H NMR (DMSO-d6): δ 8.63 (s, 2H),7.49-7.47 (m, 2H), 7.34-7.30 (t, 2H), 7.21-7.17 (m, 1H), 5.60 (s, 1H),3.76 (s, 2H), 3.64-3.62 (m, 8H), 3.35 (m, 2H), 2.26-2.20 (m, 3H),2.12-2.08 (m, 2H), 1.90-1.88 (m, 7H), 1.79-1.73 (m, 2H), 1.65-1.63 (m,1H), 1.52-1.44 (m, 3H). Mass: m/z 507.3 (M+H)⁺.

Synthesis of SC_3100:CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-onehydrochloride

Step 1: tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate

In analogy to the method described for SC_3097 step 1 tert-butylpiperazine-1-carboxylate was reacted with 5-bromo-2-chloropyrimidine tobe converted into tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate.

Step 2: tert-butyl4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

K₂CO₃ (0.38 g, 2.8 mmol, 2.5 equiv.) was added to the suspension ofCIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(0.4 g, 1.12 mmol, 1 equiv.) (INT-799) and tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (0.38 g, 1.12 mmol, 1equiv.) in dioxane (25 mL) and the resulting mixture was purged withnitrogen for 5 min. Copper(I) iodide (0.21 g, 1.12 mmol, 1 equiv.) andtrans-1,2-diaminocyclohexane (0.25 g, 2.24 mmol, 2 equiv.) weresequentially added, the reaction vessel was sealed and the reactionmixture was stirred for 10 h at 130° C. The reaction mixture was cooleddown to RT and diluted with EtOAc (20 mL) and aq. ammonia (10 mL). Theorganic product was extracted with e EtOAc (2×50 mL). The combinedorganic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure. Purification of the residue bycolumn chromatography on silica gel (100-200 mesh) (60-70% EtOAc inpetroleum ether) afforded 0.5 g (72%) of tert-butyl4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylateas an off white solid (TLC system: 1:1 EtOAc/pet ether. R_(f): 0.3).

Step 3:CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-onehydrochloride (SC_3100)

4N HCl in dioxane (2 mL) was added to tert-butyl4-(5-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate(0.15 g, 0.24 mmol). The resulting mixture was stirred at 0° C. for 6 hand then concentrated under reduced pressure to give a pale yellow solidwhich was triturated with n-pentane and lyophilized with water for 16 hto yield 0.14 g ofCIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-onehydrochloride (SC_3100) as a pale yellow solid. ¹H NMR (DMSO-d6): δ10.42 (br s, 1H), 9.34 (br s, 2H), 8.63 (s, 2H), 7.70-7.68 (m, 2H),7.54-7.50 (m, 3H), 3.88-3.86 (m, 4H), 3.77 (m, 4H), 3.16-3.11 (m, 6H),2.52-2.49 (m, 6H), 2.47 (m, 2H), 2.10-2.07 (m, 2H), 2.00-1.95 (t, 2H),1.87-1.81 (m, 3H), 1.70-1.68 (m, 2H), 1.58 (m, 1H). Mass: m/z 520.3(M+H)⁺.

Synthesis of SC_3103:CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Cs₂CO₃ (2 g, 6.451 mmol) was added to an argon purged solution ofCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-987) (1.1 g, 3.225 mmol, 1 equiv.). Xantphos (279 mg, 0.483 mmol,0.15 equiv.), Pd₂(dba)₃ (295 mg, 0.322 mmol, 0.1 equiv.) and5-bromo-4-methyl-2-(trifluoromethyl)pyridine (774 mg, 3.225 mmol, 1equiv.) in 1,4-dioxane (55 mL). The mixture was purged again with argonfor 15 min. The reaction mixture was stirred at 90° C. for 18 h. thencooled down to RT, filtered through Celite and washed with EtOAc (80mL). The filtrate was concentrated under reduced pressure. The resultingresidue was purified by flash chromatography (neutral alumina, 0-3%methanol in DCM) to afford 0.6 g (37%) ofCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3103) as an off white solid. (TLC system: 5% MeOH in DCM; Rf: 0.5).¹H NMR (DMSO-d6): δ 8.56 (s, 1H), 7.80 (s, 1H), 7.34-7.24 (m, 5H), 3.71(s, 2H), 3.17 (d, 2H), 2.70-2.56 (m, 3H), 2.31 (s, 3H), 2.17-2.11 (m,2H), 2.03-2.00 (m, 8H), 1.82-1.73 (m, 4H), 1.54-1.41 (m, 4H). Mass: m/z501.3 (M+H)⁺.

Synthesis of SC_3105:CIS-1-(cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaH (60%/o in mineral oil) (36.80 mg, 0.92 mmol) was added portionwiseto the solution ofCIS-8-(dimethylamino)-3-(4-(methylsulfonyl)phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(200 mg, 0.46 mmol, prepared from INT-976 and1-bromo-4-(methylsulfonyl)benzene by analogy with SC_3103) in DMF (30mL) at 0° C. under argon atmosphere and the resulting mixture wasstirred for 10 min. (Bromomethyl)cyclopropane (122 mg, 0.92 mmol) wasadded dropwise at 0° C., ice bath was removed and the reaction mixturewas further stirred for 4 h at room temperature. The reaction progresswas monitored by TLC. The reaction mixture was diluted with water (30mL) and the precipitated solid was filtered Purification by columnchromatography (silica gel 100-200 mesh, 50-60% ethyl acetate in hexaneas eluent) to get 80 mg (35%) ofCIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(4-(methylsulfonyl)phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3105) as off white solid (TLC system: 10% MeOH in DCM; Rf: 0.70). 1HNMR (CDCl3): δ 7.85-7.83 (d, 2H), 7.73-7.71 (d, 2H), 7.39-7.36 (m, 2H),7.32-7.27 (m, 3H), 3.64 (s, 2H), 3.20 (d, 2H), 3.00 (s, 3H), 2.75-2.71(m, 2H), 2.43-2.36 (m, 2H), 2.07 (s, 6H), 1.57 (nm, 2H), 1.50 (m, 2H),1.11-1.06 (mu, 1H), 0.59-0.54 (m, 2H), 0.41-0.37 (m, 2H). Mass: m/z482.2 (M+H)⁺.

Synthesis of SC_3109:CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide

Step 1:CIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile

In analogy to the method described for SC_3103CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-onwas reacted with 2-bromobenzonitrile to be converted intoCIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile.

Step 2:CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamideSC_3109

CIS-2-[8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]benzonitrile(57.0 mg, 1.0 equiv.) was dissolved in DMSO (1.6 mL), hydrogen peroxide(0.167 mL, 14.0 equiv., 30 mass % in water solution) and K₂CO₃ (32.4 mg,2.0 equiv.) were added and the reaction mixture was stirred at RT for 18h. The reaction mixture was then quenched with 10 mL water, extractedwith DCM (3×10 mL), the combined organic extracts were dried over Na₂SO₄and concentrated under reduced pressure (24 mg crude product). Theaqueous phase was concentrated to dryness (91 mg), suspended in DCM, theprecipitate was filtered off and the organic solution was concentratedunder reduced pressure to give additional 56 mg of the crude product.The combined crude product was purified by column chromatography onsilica gel (DCM/EtOH 95/5) to give 37 mg (62%) ofCIS-2-[8-dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide(SC_3109) as a white solid. ¹H NMR (600 MHz, DMSO) δ 7.52-7.48 (s, 1H),7.47-7.31 (m, 7H), 7.29-7.23 (m, 1H), 7.25-7.22 (s, 1H), 7.24-7.18 (m,1H), 3.68-3.65 (s, 3H), 3.13-3.10 (s, 2H), 3.09-3.02 (m, 2H), 2.71-2.65(m, 2H), 2.21-2.12 (m, 2H), 2.09-1.99 (m, 2H), 2.02-1.98 (s, 6H),1.97-1.86 (m, 4H), 1.77-1.67 (m, 1H), 1.64-1.52 (m, 3H), 1.44-1.36 (td,2H). Mass: m/z 505.32 (M+H)⁺.

Synthesis of SC_3112:CIS-2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile

Step 1:CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile

In analogy to the method described for SC_3103 1-bromo-2-cyanobenzenewas reacted withCIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)to be converted intoCIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile.

Step 2:CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile

To a solution ofCIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile(500 mg, 1.336 mmol, 1.0 equiv.) in DMSO (16 ml) was added sodiumhydroxide (213 mg, 5.334 mmol, 4.0 equiv.) and the mixture was stirredat 60° C. for 30 min. A solution of 1-oxa-spiro[2.3]hexane (237 mg, 6.68mmol, 5.0 equiv.) in DMSO (4 ml) was added at RT and the reactionmixture was stirred at 55° C. for 16 h. The reaction mixture was dilutedwith water (100 ml) and extracted with EtOAc (100 ml). The organic layerwas washed with water (50 ml) and brine (50 ml), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (EtOAc/Hexane, 7/3) to yieldCIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile(200 mg, 0.436 mmol, 32%) as an off white solid. Mass: nm/z 459.4 (M+H)⁺

Step 3:CIS-2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile(SC_3112)

In analogy to the method described for SC_3099CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrilewas reacted with N-iodosuccinimide to be converted intoCIS-2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile(SC_3112). Yield: 29%. ¹H NMR (DMSO-d6, 400 MHz), δ (ppm)=7.75 (dd, 1H,J=7.76 Hz, 1.16 Hz), 7.70-7.65 (m, 1H), 7.50 (d, 1H, J=8.16 Hz),7.44-7.42 (m, 2H), 7.35-7.25 (m, 3H), 7.17-7.15 (m, 1H), 5.49 (s, 1H),3.85 (s, 2H), 3.32 (s, 2H), 2.29-2.23 (m, 2H), 2.12-2.23 (m, 2H), 1.87(bs, 6H), 1.73-1.46 (m, 6H). Mass: m/z 445.26 (M+H)⁺.

Synthesis of SC_3120:CIS-8-(dimethylamino)-3-(2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-989) (100 mg, 0.259 mmol) was placed into a reaction vial formicrowave reactor (5 mL), the vial was flushed with nitrogen, anhydrousn-butanol (50 equiv., 13.0 mmol, 1.2 mL), diisopropylethylamine (5equiv., 1.30 mmol, 0.224 mL) and piperazine-2-one (1.2 equiv., 0.311mmol, 31 mg) were added, the vial was sealed and the reaction mixturewas stirred for 2.5 h at 140° C. (conventional heating). The reactionmixture was cooled down, transferred into a 1-neck flask andconcentrated under reduced pressure. The resulting residue (128 mg) waspurified by flash chromatography on aluminium oxide (neutral) (DCM/MeOHgradient 100/0 to 97/3) to yield 65 mg (56%)CIS-8-(dimethylamino)-3-(2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro-[4.5]decan-2-one(SC_3120). ¹H NMR (600 MHz, DMSO) δ 8.60 (s, 2H), 8.01 (s, 1H), 7.46 (s,1H), 7.43-7.30 (m, 4H), 7.27 (td, 1H), 4.09 (s, 2H), 3.91-3.75 (m, 2H),3.62-3.40 (m, 2H), 3.30-3.09 (m, 2H), 2.61-2.51 (m, 2H), 2.44-2.25 (m,2H), 1.97 (s, 6H), 1.93-1.80 (m, 2H), 1.55-1.41 (m, 2H). Mass: m/z437.27 (M+H)⁺.

Synthesis of SC_3129:CIS-3-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-989) (1 equiv., 0.47 mmol, 180 mg), Pd(PPh₃)₄ (0.1 equiv., 0,047mmol, 54 mg) and (3-cyanophenyl)boronic acid (1.5 equiv., 0.70 mmol, 103mg) were dissolved in degassed dry tetrahydrofurane (9.5 mL) and sodiumcarbonate 1M aq. sol. (1.9 equiv., 0.89 mmol, 0.89 mL) was added. Theresulting clear reaction mixture was stirred overnight at 70° C.Additional portion of Pd(PPh₃)₄ (0.1 equiv., 0.047 mmol, 54 mg) wasadded and the reaction was stirred further 12 h at 70° C. The reactionmixture was diluted with EtOAc (50 mL), stirred for 10 min, theprecipitate was filtered off and the filtrate was concentrated underreduced pressure. The resulting residue (285 mg) was purified by flashchromatography on silica gel (gradient DCM/MeOH, 100/0 to 80/20) toyield 130 mg (62%) ofCIS-3-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile(SC_3129). ¹H NMR (600 MHz, DMSO) δ 9.13 (s, 2H), 8.60 (dp, 2H), 7.93(dt, 1H), 7.88 (s, 1H), 7.72 (dd, 1H), 7.42-7.35 (m, 5H), 7.28 (d, 1H),3.73 (s, 2H), 2.01-1.91 (m, 2H), 1.98 (s, 10H), 1.57-1.48 (m, 2H). Mass:m/z 453.24 (M+H)⁺.

Synthesis of SC_3130:CIS-8-(dimethylamino)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazin-5-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3124) (100 mg, 0.23 mmol) was dissolved in DCM (150 equiv., 34 mmol,2.2 mL) under nitrogen atmosphere. To the resulting solution4-dimethylaminopyridine (0.05 equiv., 0.012 mmol, 1.4 mg) anddiisopropylethylamine (3 equiv., 0.67 mmol, 0.119 mL) were added and themixture was cooled to 0° C. Methanesulfonylchloride (2 equiv., 0.46mmol, 0.036 mL) was added, ice bath was removed and the reaction mixturewas stirred for 2 h at RT. The reaction mixture was quenched with water(5 mL), diluted with DCM (10 mL), the resulting brown suspension wasfiltered through a glass filter, the filtrate transferred to aseparating funnel, the organic phase separated and the aqueous phaseextracted with DCM (2×10 mL). The combined organic phases were driedover MgSO₄ and concentrated under reduced pressure. The resultingresidue (81 mg) was purified by flash chromatography on aluminium oxide(gradient DCM/EtOH 97/3 to 96/4) to yield 51 mg (43%) ofCIS-8-(dimethylamino)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro-[4.5]decan-2-one(SC_3130). ¹H NMR (600 MHz, DMSO) δ 8.59 (s, 2H), 7.46 (s, 1H), 7.39 (d,1H), 7.37 (s, 3H), 7.28 (d, 1H), 3.79-3.74 (m, 4H), 3.54 (s, 2H),3.18-3.13 (m, 4H), 2.87 (s, 3H), 2.43-2.32 (m, 2H), 1.97 (s, 6H),1.92-1.87 (m, 2H), 1.51-1.41 (m, 2H). Mass: m/z 514.26 (M+H)⁺.

Synthesis of SC_3132:CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS4-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for SC_3099CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3245) was reacted with N-iodosuccinimide to be converted intoCIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

NaH (60% in mineral oil) (296.3 mg, 7.407 mmol, 1.5 equiv.) was addedportionwise to the solutionCIS-8-(methylamino)-8-phenyl-3-(2-(trifluromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(2 g, 4.938 mmol, 1 equiv.) in DMF (20 mL) at 0° C. under argonatmosphere and the resulting mixture was stirred for 10 min.1-(Bromomethyl)-4-methoxybenzene (1.092 g, 5.432 mmol, 1.1 equiv.) wasadded dropwise. The reaction mixture was allowed to warm up to RT andstirred for 16 h. The reaction progress was monitored by LCMS. Thereaction mixture was diluted with water (150 mL) and the organic productwas extracted with EtOAc (3×60 mL). The combined organic extracts weredried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography (silica gel230-400 mesh; 0-4% MeOH/DCM) to afford 2 g (77%) ofCIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-oneas an off white solid (TLC system 5% MeOH in DCM Rf: 0.55).

Step 3:CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

(Bromomethyl)cyclopropane (0.461 mL, 4.762 mmol, 5 equiv.) was addeddropwise to a mixture of CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-pheyl-3-(2-(trifluoroethyl)pyrimidin-5-yl)-1,3-diazaspiro-[4.5]decan-2-one(500 mg, 0.952 mmol, 1 equiv.) and K₂CO₃ (657 mg, 4.762 mmol, 5 equiv.)in acetonitrile (20 mL) at RT under argon atmosphere. The reactionvessel was sealed and the mixture was stirred at 95° C. for 24 h.Reaction progress was monitored by LCMS. The reaction mixture wasdiluted with water (50 mL) and the organic product was extracted withEtOAc (2×50 mL). The combined organic extracts were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (silica gel 230-400 mesh; 0-40%EtOAc/petroleum ether) to afford 220 mg (39%) ofCIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-oneas an off white solid (TLC 50% EtOAc in petroleum ether, Rf: 0.65) and230 mg of the unreacted starting material.

Step 4:CIS-8-((cyclopropylmethyl)amino)-8-phenyl-3-(2-(trifluormethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3132)

TFA (4.2 mL) was added drop wise to a solution ofCIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(210 mg, 0.363 mmol) in DCM (0.05 mL) at 0° C. under argon atmosphere.The reaction mixture was allowed to warm up to RT and stirred for 16 h.The reaction progress was monitored by LCMS. The excess of TFA wasevaporated under reduced pressure and the residual amount of TFA wasremoved as an azeotropic mixture with DCM (2×5 mL). The crude productwas purified by preparative HPLC to yield 105 mg (63%) ofCIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3132) as an off white solid (TLC system 50% EtOAc in pe ether, Rf:0.35). ¹H NMR (DMSO-d6): δ 9.17 (s, 2H), 8.10 (br s, 1H), 7.35-7.33 (m,4H), 7.25-7.22 (m, 1H), 3.72 (s, 2H), 2.43 (m, 2H), 2.13 (s, 3H),1.97-1.82 (m, 6H), 1.49 (m, 2H), 0.75-0.71 (m, 1H), 0.41-0.39 (m, 2H),0.06-0.01 (m, 2H). Mass: m/z=460.2 (M+H).

Synthesis of SC_3133:CIS-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

1-Methylpiperazine (2 equiv., 0.5 mmol, 55 μL) and[5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonyl]oxylithium(INT-990) (100 mg, 0.25 mmol) were suspended in DCM (1.6 mL),triethylamine (10 equiv., 2.5 mmol, 336 μL) and propylphosphonicanhydride (?50 wt. % solution in ethyl acetate) (2 equiv., 0.5 mmol, 297μL) were sequentially added and the reaction mixture was stirred at RTfor 2 h. The resulting mixture was quenched with 2M aq. NaOH (2 mL),organic phase was separated and aqueous phase was extracted withdichloromethane (3×10 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated under reduced pressure. The residue (88 mg) wasdissolved in 3 mL DCM and 6 mL pentane were slowly added. The resultingmixture was stirred for 30 min. The precipitate was filtered off anddried under reduced pressure to give 69 mg (58%) ofCIS-8-dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-3-diazaspiro[4.5]decan-2-one(SC_3133). ¹H NMR (600 MHz, DMSO) δ 9.03 (s, 2H), 7.87 (s, 1H),7.42-7.34 (m, 5H), 7.28 (d, 1H), 3.69 (s, 2H), 3.62 (dd, 2H), 3.17-3.12(m, 2H), 2.57-2.51 (m, 2H), 2.36 (t, 2H), 2.25-2.21 (m, 2H), 2.21 (s,3H), 1.98-1.89 (m, 2H), 1.96 (s, 6H), 1.56-1.46 (m, 2H). Mass: m/z478.29 (M+H)⁺.

Synthesis of SC_3146:CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxamide

MethylCIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate(INT-990) (100 mg, 0.244 mmol) was dissolved in 7N NH₃ in methanol (25equiv. NH₃, 0.9 mL) in a microwave reactor vial. The reaction vessel wassealed, the reaction mixture was stirred for 5 days at RT and thenconcentrated under reduced pressure. The residue was purified by flashchromatography on neutral aluminum oxide (DCM/EtOH, gradient 90/10 to74/26) to yield 38 mg (39%) ofCIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxamide(SC_3140). ¹H NMR (600 MHz. DMSO) δ 9.07 (s, 2H), 8.02 (d, 1H), 7.93 (s,1H), 7.59-7.55 (m, 1H), 7.38 (d, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H),2.49-2.37 (m, 2H), 1.99-1.92 (m, 8H), 1.88-1.75 (m, 2H), 1.56-1.45 (m,2H). Mass: m/z 395.22 (M+H)⁺.

Synthesis of SC_3146: methylCIS-2-(4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazin-1-yl)acetate

CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3124) (200 mg, 0.46 mmol) was dissolved in dry acetonitrile (5 mL)under nitrogen atmosphere, K₂CO₃ (1.2 equiv., 0.55 mmol, 76 mg) andmethyl-2-chloroacetate (1.5 equiv., 0.69 mmol, 0.06 mL) weresequentially added and the reaction mixture was stirred at reflux for 5h. A new portion of methyl-2-chloroacetate (1.5 equiv., 0.69 mmol, 0.06mL) was added and the reaction mixture was stirred at reflux overnight.The reaction mixture was concentrated under reduced pressure. Theresidue was suspended in DCM, the precipitate was filtered off andwashed with DCM. The combined filtrate was concentrated under reducedpressure to give 106 mg of crude product. Flash chromatography on silicagel (eluent DCM/EtOH gradient 98/2 to 96/4) yielded 168 mg (72%) ofmethylCIS-2-(4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazin-1-yl)acetate(SC_3146). ¹H NMR (600 MHz, DMSO) δ 8.54 (s, 2H), 7.42 (s, 1H), 7.37 (m,4H), 7.27 (m, 1H), 3.63 (t, 7H), 3.52 (s, 2H), 3.27 (s, 2H), 2.54 (t,4H), 2.45-2.30 (m, 2H), 1.96 (s, 6H), 1.93-1.83 (m, 4H), 1.52-1.42 (m,2H). Mass: m/z 508.4 (M+H)⁺.

Synthesis of SC_3162:CIS-8-(dimethylamino)-8-phenyl-3-(2-(pyridin-2-yl)pyrimidin-5-yl)-1,3-diazaspiro[4]decan-2-one

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-989) (200 mg, 0.52 mmol), tributyl(2-pyridyl)stannane (1.5 equiv.,0.78 mmol, 286 mg) and Pd(PPh₃)₄ (0.1 equiv., 0.052 mmol, 60 mg) weredissolved in degassed anhydrous DMF (150 equiv., 77.7 mmol, 6 mL) undernitrogen atmosphere. Cesium fluoride (2.2 equiv., 1.14 mmol, 173 mg) wasadded and the reaction mixture was stirred at 90° C. overnight. Theresulting suspension was cooled down to RT, diluted with water (10 mL),extracted with ethylacetate (30 mL), then DCM (30 mL), the DCM phase wasdried over MgSO₄ and concentrated under reduced pressure to give 320 mgof crude product. Flash chromatography on silica gel (eluent DCM/0.1NNH₃ in MeOH, gradient 95/5 to 70/30) yielded 72 mg (33%) ofCIS-8-(dimethylamino)-8-phenyl-3-(2-(pyridin-2-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3162). ¹H NMR (600 MHz, DMSO) δ 9.13 (s, 2H), 8.71-8.67 (m, 1H),8.30 (d, 1H), 7.92 (td, 1H), 7.86 (s, 1H), 7.46 (dd, 1H), 7.43-7.35 (m,1H), 7.31-7.25 (m, 1H), 3.73 (s, 2H), 2.48-2.33 (m, 2H), 2.00-1.78 (m,10H), 1.57-1.47 (m, 2H). Mass: m/z 429.2 (M+H)⁺.

Synthesis of SC_3169:CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)aceticacid

Step 1:CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile

In analogy to the method described for SC_3103CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)was reacted with 2-(2-bromophenoxy)acetonitrile to be converted intoCIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile.

Step 2:CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)aceticacid (SC_3169)

CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile(134 mg, 0.331 mmol) was dissolved in conc. aq. HCl (1.4 mL, 50 equiv.).The reaction mixture was heated to 100° C. for 2 h and cooled down toRT. The precipitate was filtered off, washed with water (2×) and driedunder reduced pressure to give 31 mg (22%) ofCIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)aceticacid (SC_3169). ¹H NMR (600 MHz, DMSO) δ 7.75-7.71 (m, 1H), 7.59-7.48 (m4H), 7.27 (dd, 1H), 7.15 (ddd, 1H), 6.97-6.90 (m, 2H), 4.65 (s, 2H),3.43 (s, 2H), 2.70 (d, 2H), 2.56 (s, 6H), 2.31 (t, 2H), 1.93-1.86 (m,2H), 1.33-1.22 (nm, 2H). Mass: m/z 424.2 (M+H)⁺.

Synthesis of SC_3173:CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.3]decan-2-one

Step 1: CIS-tert-butyl4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate

In analogy to the method described for SC_3133 lithiumCIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate (INT-990) wasreacted with 1-(tert-butoxycarbonyl)piperazine to be converted intoCIS-tert-butyl4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate.

Step 2:CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3173)

CIS-tert-butyl4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate(230 mg, 0.41 mmol) was dissolved in TFA (2.2 mL, 28.6 mmol, 70 equiv.).The reaction mixture was stirred at RT for 2.5 h and then concentratedunder reduced pressure. The residue was dissolved in DCM and aq. satNa₂CO₃ was added (until pH 10). The organic phase was separated and theaq. phase was extracted with DCM (2×). The combined organic extractswere dried over MgSO₄ and concentrated under reduced pressure.Recrystallization of the residue from DCM/pentane gave 105 mg (56%) ofCIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-5-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-on(SC_3173). ¹H NMR (600 MHz, DMSO) δ 9.04 (s, 2H), 7.89 (s, 1H),7.42-7.32 (m, 4H), 7.31-7.26 (m, 1H), 3.69 (s, 2H), 3.65 (t, 2H), 3.21(t, 2H), 2.90 (t, 2H), 2.79-2.74 (m, 2H), 2.43 (s, 2H), 1.98 (s, 9H),1.89-1.75 (m, 1H), 1.53-1.47 (m, 2H). Mass: m/z 464.3 (M+H)⁺.

Synthesis of SC_3182:CIS-8-(dimethylamino)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Et₃N (0.39 g, 3.89 mmol) was added to the solution ofCIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-989) (0.5 g, 1.29 mmol) and piperidin-4-ol (0.32 g, 3.24 mmol) inDMF (10 mL) at RT. The reaction mixture was stirred at 130° C. for 16 h,cooled down to RT and concentrated under reduced pressure. The residuewas diluted with 10% aq. NaOH and the organic product was extracted with1/9 v/v MeOH/DCM. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified bypreparative TLC using 10% MeOH/DCM as eluent to afford 130 mg ofCIS-8-(dimethylamino)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC 3182) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.1).¹H NMR (DMSO-d6): δ 8.50 (s, 2H), 7.39-7.26 (m, 6H), 4.68 (d, 1H),4.19-4.16 (m, 2H), 3.69-3.67 (m, 1H), 3.51 (s, 2H), 3.14 (t, 2H), 2.33(m, 2H), 1.94-1.71 (m, 12H), 1.45 (m, 2H), 1.30-1.23 (m, 2H). Mass: m/z451.2 (M+H)⁺.

Synthesis of SC_3186:CIS-8-(dimethylamino)-3-(3-methylpyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Compound was synthesized within a parallel array. An argon-flushed dryreaction vessel equipped with a septum was loaded with the solutions ofINT-976 (0.1 M, 1 mL) and 1-bromo-2-methylbenzene (0.15 M, 1 mL) indioxane. To the resulting mixture Cs₂CO₃ (200 μmol). XantPhos (10 μmol)and Pd₂(dba)₃ (5 μmol) were added. The reaction vessel was flushed withargon once again, sealed and the reaction mixture was shaken at 100° C.overnight. The resulting mixture was cooled down to RT and the solventwas removed under reduced pressure. The residue was taken up in 3 mLdichloromethane and 3 mL water, the organic phase was separated, theaqueous phase was extracted with dichloromethane (2×3 mL). Combinedorganic phases were concentrated under reduced pressure. The residue waspurified by HPLC to giveCIS-8-(dimethylamino)-3-(3-methylpyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3186). Mass: m/z 363.2 (M+H)⁺.

Synthesis of SC_3208:CIS4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)indolin-2-one

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-989) (150 mg, 0.38 mmol), Pd(t-Bu₃P)₂ (0.1 equiv., 0.02 mmol, 10mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2equiv., 0.78 mmol, 201 mg) were dissolved in degassed anhydrous THF (80equiv., 31 mmol, 2.5 mL) and 1M aq. Na₂CO₃ (5.5 equiv., 2.14 mmol, 2.14mL) was added. The resulting mixture was stirred at 60° C. for 8 h andthen at RT overnight. The reaction mixture was diluted with water untilprecipitation occurred. The precipitate was filtered off, suspended in30 mL DCM, filtered off again, washed with pentane (5 mL) and driedunder reduced pressure to give 143 mg (76%) ofCIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)indolin-2-one(SC_3208). ¹H NMR (600 MHz, DMSO) δ 10.45 (s, 1H), 9.10 (s, 2H), 7.87(d, 1H), 7.84-7.80 (m, 1H), 7.39 (d, 5H), 7.29 (dt, 2H), 6.91 (d, 1H),3.82 (s, 2H), 3.72 (s, 2H), 2.41 (d, 2H), 2.03-1.74 (m, 9H), 1.60-1.44(m, 3H). Mass: m/z 484.26 (M+H)⁺.

Synthesis of SC_3221:CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for SC_3103 2-methoxyethanamine wasreacted withCIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-989) to be converted intoCIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3221)

BBr₃ (1M in DCM) (2.2 mL, 2.22 mmol) was added to the solution ofCIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(0.55 g, 1.06 mmol) in DCM (20 mL) at −78° C. over 15 min. The reactionmixture was stirred at RT for 4 h, then quenched with water andconcentrated under reduced pressure. The residue was purified bypreparative reverse phase HPLC to afford 82 mg (19%0) ofCIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3221) (TLC system: 10% MeOH in DCM (Ammonia atmosphere); Rf: 0.3).¹H NMR (DMSO-d6): δ 8.41 (s, 2H), 7.39-7.24 (m, 6H), 6.70 (t, 1H), 4.64(br, s, 1H), 3.50-3.45 (m, 4H), 3.28-3.25 (m, 2H), 2.37 (br m, 2H),1.94-1.86 (m, 10H), 1.45 (m, 2H). Mass: m/z 411.2 (M+H)⁺

Synthesis of SC_3224:CIS-3-(2-(1-indazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

K₂CO₃ (0.53 g, 3.89 mmol) was added to the solution ofCIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazasprio[4.5]decan-2-one(500 mg, 1.29 mmol) and 1H-indazole (306 mg, 2.59 mmol) in DMF (10 mL).The reaction mixture was stirred at 140° C. for 48 h, cooled down to RTand concentrated under reduced pressure. The residue was diluted withDCM (50 mL), filtered through Celite and the filtrate was concentratedunder reduced pressure. The residue was purified by flash chromatographyusing neutral alumina (0-10% MeOH/DCM) followed by reverse phase HPLC toafford 77 mg (13%) ofCIS-3-(2-(1H-indazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3224) as off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.6). ¹HNMR (DMSO-d6): δ 9.10 (s, 2H), 8.57-8.55 (d, 1H), 8.41 (s, 1H),7.89-7.87 (d, 1H), 7.82 (br s, 1H), 7.57-7.53 (t, 1H), 7.39-7.28 (m,6H), 3.72 (s, 2H), 2.45 (m, 2H), 1.98-1.93 (m, 10H), 1.52 (m, 2H). Mass:m/z 468.2 (M+H)⁺.

Synthesis of SC_3235: CIS-methyl2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetate

CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)aceticacid (120 mg, 0.28 mmol) was dissolved in methanol (1.4 mL, 125 equiv.)and thionyl chloride (4 equiv., 1.13 mmol, 83 μL) was added dropwise.The reaction mixture was stirred at RT overnight, diluted with aq. sat.NaHCO₃ and extracted with DCM (3×). The combined organic phases weredried over MgSO₄ and concentrated under reduced pressure. The residue(112 mg) was purified by flash chromatography on silica get (gradientDCM/MeOH 97/3 to 88/12) to give 92 mg (74%) of CIS-methyl2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetate(SC_3235). ¹H NMR (600 MHz, DMSO) δ 7.40-7.33 (n, 4H), 7.29 (dd, 1H),7.28-7.24 (m, 1H), 7.13 (td, 1H), 6.99-6.91 (m, 2H), 4.76 (s, 2H), 3.67(s, 3H), 3.55 (s, 2H), 2.45-2.26 (m, 2H), 2.07 (s, 2H), 1.98 (s, 6H),1.94-1.75 (m, 4H), 1.52-1.45 (m, 2H). Mass: m/z 438.2 (M+H)⁺.

Synthesis of SC_3238:CIS-2-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-989) (240 mg, 0.56 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I) complex withdichloromethane (0.05 equiv., 0.028 mmol, 23 mg) and(2-cyanophenyl)boronic acid (1.125 equiv., 0.63 mmol, 92 mg) weredissolved in degassed 1,2-dimethoxyethane (100 equiv., 56 mmol, 5.8 mL)and Cs₂CO₃ (3.3 equiv., 1.84 mmol, 600 mg) in water (175 equiv., 98mmol, 1.8 mL) was added. The resulting clear reaction mixture wasstirred 3 days at 60° C. The reaction mixture was diluted with water (15mL) and extracted with EtOAc (2×15 mL). Combined organic phases weredried over MgSO₄ and concentrated under reduced pressure. The residue(355 mg) was purified by flash chromatography on silica get (gradientDCM/MeOH 95/5 to 70/30) to give 60 mg of product, which was furtherpurified by HPLC to give 15.4 mg (6%) ofCIS-2-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile(SC_3238). ¹H NMR (600 MHz, DMSO) δ 9.17 (s, 2H), 8.27 (dd, 1H), 7.94(dd, 1H), 7.81 (td, 1H), 7.65 (td, 1H), 7.42-7.35 (m, 5H), 7.28 (ddt,1H), 3.75 (s, 2H), 2.49-2.34 (m, 1H), 2.00-1.76 (m, 1H), 1.55-1.51 (m,2H). Mass: m/z 453.24 (M+H)⁺.

Synthesis of SC_3239:CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Microwave reactor vial was loaded withCIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-989) (250 mg, 0.65 mmol), flushed with nitrogen, 7N solution of NH₃in methanol (108 equiv., 70 mmol, 10 mL) and dioxane (37 equiv., 24mmol, 2 mL) were added, the vial was sealed and the reaction mixture wasstirred at 115° C. for 12 h in the microwave reactor. The reactionmixture was then cooled down to 4° C. overnight. The precipitate formedwas filtered off, washed with DCM (small amount), water (2×), ether (2×)and dried under reduced pressure to give 180 mg (76%) ofCIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3239) as an off-white solid. ¹H NMR (600 MHz, DMSO) δ 8.39 (s, 2H),7.40-7.32 (m, 5H), 7.26 (tt, 1H), 6.25 (s, 2H), 3.51 (s, 2H), 2.37 (s,2H), 2.07 (s, 2H), 1.96 (s, 6H), 1.94-1.68 (m, 4H), 1.47 (d, 2H), Mass:m/z 367.23 (M+H)⁺.

Synthesis of SC_3240:CIS—N-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)cyclopropanecarboxamide

CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3239) (50 mg, 0.14 mmol) and 4-dimethylaminopyridine (1.3 equiv.,0.18 mmol, 22 mg) were dissolved in dry pyridine (200 equiv., 27 mmol,2.2 mL) under nitrogen atmosphere. Cyclopropancarbonyl chloride (1.3equiv., 0.18 mmol, 16 μL) was added in one portion and the reactionmixture was stirred at RT for 3 h. Additional portion ofcyclopropancarbonyl chloride (3 equiv., 0.42 mmol, 37 μL) was added andthe reaction mixture was stirred at 90° C. for 1 h. The reaction mixturewas diluted with water (5 mL) and aq. sat. NaHCO₃ (5 mL), extracted withDCM (3×10 mL), organic phases were washed with brine, dried over Na₂SO₄and the solvent was removed under reduced pressure. The residue wassuspended thoroughly in 3 mL DCM, the precipitate was filtered off,washed with ether and dried under reduced pressure to give 47 mg (79%)ofCIS—N-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)cyclopropanecarboxamide(SC_3240) as a white solid. ¹H NMR (600 MHz, DMSO) δ 10.66 (s, 1H), 8.81(s, 2H), 7.67 (s, 1H), 7.41-7.33 (m, 4H), 7.31-7.21 (m, 1H), 3.62 (s,2H), 2.45-2.32 (m, 2H), 2.01 (td, 1H), 1.96 (s, 6H), 1.93-1.78 (m, 3H),1.52-1.47 (m, 2H), 0.82-0.72 (m, 4H). Mass: m/z 435.3 (M+H)⁺.

Synthesis of SC_3242:CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: 4-(5-bromopyrimidin-2-yl)piperazine

In analogy to the method described for SC_3097 step 15-bromo-2-chloro-pyridine was reacted with piperazine to be convertedinto 4-(5-bromopyrimidin-2-yl)piperazine.

Step 2:CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro[4.3]decan-2-one (SC_3242)

CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)(80 mg, 0.29 mmol), 4-(5-bromopyrimidin-2-yl)piperazine (2 equiv., 0.56mmol, 142 mg) and potassium phosphate (4 equiv., 1.17 mmol, 248 mg) weresuspended in N,N′-dimethylethylenediamine (18 equiv., 5.27 mmol, 0.6 mL)under nitrogen atmosphere. The reaction mixture was stirred at 80° C.for 2 h. diluted with water (10 mL) and extracted with DCM (3×15 mL).The combined organic phases contained a precipitate which was filteredoff, washed with isopropanol and dried under reduced pressure to give 79mg (62%) ofCIS-8-(dimethyl-amino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3242). ¹H NMR (600 MHz, DMSO) δ 8.15 (d, 1H), 7.85(dd, 1H), 7.41-7.33 (m, 4H), 7.32-7.23 (m, 2H), 6.74 (d, 1H), 3.51 (s,2H), 3.30-3.25 (m, 4H), 2.78-2.73 (m, 4H), 2.43-2.31 (m, 2H), 1.96 (s,6H), 1.93-1.79 (m, 4H), 1.50-1.42 (m, 2H). Mass: m/z 435.3 (M+H)⁺.

Synthesis of SC_3275:CIS-8-(ethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

CIS-8-amino-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(70 mg, 0.15 mmol) was dissolved in anhydrous DCM (3.8 mL) undernitrogen atmosphere. Acetic acid (0.1 equiv., 0.015 mmol, 0.8 μL) andacetaldehyde (1.1 equiv., 0.16 mmol, 9 μL) were sequentially added andthe resulting mixture was stirred at RT for 1 h. Sodiumtriacetoxyborohydride (2 equiv., 0.29 mmol, 62 mg) was added and thereaction mixture was stirred at RT overnight and then at 50° C. for 5 h.Additional amounts of acetaldehyde (1.1 equiv., 0.16 mmol, 9 μL) andsodium triacetoxyborohydride (2 equiv., 0.29 mmol, 62 mg) were added andthe reaction mixture was stirred further 24 h at 50° C. The resultingmixture was cooled down to RT, quenched with aq. sat. NaHCO₃ until pH>7,diluted with water and extracted with DCM (3×). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The residue (70 mg) was purified by flash chromatography on silica gel(DCM/EtOH gradient 99/1 to 95/5) to yield 43 mg (58%) ofCIS-8-(ethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3275). ¹H NMR (600 MHz, DMSO) δ 9.26 (s, 2H), 7.55-7.49 (m, 2H),7.33 (t, 2H), 7.21 (d, 1H), 3.92 (s, 2H), 2.38 (td, 2H), 2.17-2.06 (m,3H), 2.00-1.87 (m, 4H), 1.81 (td, 2H), 1.72-1.64 (m, 1H), 1.60-1.50 (m,1H), 1.49-1.43 (m, 2H), 0.99 (t, 3H). Mass: m/z 504.3 (M+H)⁺

Synthesis of SC_3292 and SC_3293: enantiomer 1 and enantiomer 2 ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

Cs₂CO₃ (0.85 g, 2.61 mmol) was added to an argon purged solution ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1026) (0.3 g, 0.87 mmol). Xanthphos (45 mg, 0.087 mmol), Pd₂(dba)₃(80 mg, 0.087 mmol) and 5-bromo-2-(trifluoromethyl)pyrimidine (0.29 g,1.30 mmol) in 1,4-dioxane (15 mL). The mixture was purged with argon for5 min and stirred at 90° C. for 16 h. The reaction mixture was cooled toRT, diluted with EtOAc (20 mL), filtered through Celite and the filtratewas concentrated wider reduced pressure. The crude product was purifiedby flash chromatography (silica gel 230-400 mesh; 3% MeOH in DCM) to getthe compound which was further purified by reverse phase preparativeHPLC to afford 0.1 g (23%) ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(TLC system: 10% MeOH in DCM; Rf: 0.4) as a mixture of enantiomers.Reverse phase preparative HPLC conditions: mobile phase: 10 mM ammoniumbicarbonate in H₂O/acetonitrile; column: X-BRIDGE-C18 (150*19), 5 μmmobile phase gradient (min/%/B): 0/30, 8/82, 8.1/100, 10/100, 10.1/30,12/30; flow rate: 19 ml/min; diluent: mobile phase+THF. Enantiomericmixture ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(100 mg) was separated by chiral SFC to afford 35 mg of enantiomer 1(SC-3292) and 40 mg of enantiomer 2 (SC-3293) as off-white solids.Preparative SFC conditions: column: Chiralpak IA (250×30) mm, 5 nm %CO₂: 50.0%; % co-solvent: 50.0% (100% Methanol); total flow: 70.0 g/min;back pressure: 100.0 bar; UV: 256 nm; stack time: 13.5 min; load/inj.:9.5 mg; no. of injections: 11. SC-3292: ¹H NMR (DMSO-d6): δ 9.15 (s,2H), 8.23 (broad s, 1H), 7.37-7.25 (m, 5H), 3.68-3.58 (m, 5H), 3.37-3.36(m, 1H), 2.32 (m, 3H), 2.13-1.89 (m, 10H), 1.47 (m, 3H). SC-3293: ¹H NMR(DMSO-d6): δ 9.15 (s, 2H), 8.23 (broad s, 1H), 7.37-7.36 (m, 4H),7.26-7.24 (m, 1H), 3.68-3.56 (m, 5H), 3.37-3.36 (m, 1H), 2.31-2.28 (m,3H), 2.13-1.86 (m, 10H), 1.48 (m, 3H). Mass: m/z 490.3 (M+H)⁺.

Synthesis of SC_3313:CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-S-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine

2-Azido-5-bromo-pyrimidine (400 mg, 1.94 mmol) and ethynylcyclopropane(1.3 equiv., 2.522 mmol, 0.21 mL) were dissolved in tert-butanol (5 mL).The solutions of sodium ascorbate (0.1 equiv., 0.194 mmol, 38 mg) inwater (2.5 mL) and copper(II) sulfate pentahydrate (0.1 equiv., 0.194mmol, 48 mg) in water (2.5 mL) were sequentially added. The reactionmixture was stirred under ambient conditions for 18 h, then diluted with20 mL 1M aq. NH₄OH and extracted with EtOAc (3×30 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Crude product (510 mg) was purifiedby flash chromatography on silica gel (DCM/EtOH 99/1) to yield 143 mg of5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine as a whitesolid. Mass: m/z 266.0 (M+H)⁺.

Step 2:CIS-3-(2-(4-cyclopropyl-H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3313)

In analogy to the method described for SC_3103CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)was reacted with5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine to beconverted intoCIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3313). ¹H NMR (600 MHz, DMSO) δ 9.09 (d, 2H), 8.50 (d, 1H), 7.91 (s,1H), 7.42-7.34 (m, 2H), 7.38 (s, 3H), 7.31-7.25 (m, 1H), 3.72 (s, 2H),2.48-2.31 (m, 2H), 2.10-2.01 (m, 1H), 1.99-1.77 (m, 10H), 1.58-1.46 (m,2H), 1.00-0.91 (m, 2H), 0.84 (tt, 2H). Mass: m/z 459.3 (M+H)⁺.

Synthesis of SC_3319:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

Cs₂CO₄ (145 mg, 0.45 mmol, 2 equiv.).CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1024) (65 mg, 0.223 mmol, 1 equiv.), Xanthphos (19 mg, 0.033 mmol,0.15 equiv.), Pd₂(dba)₃ (10 mg, 0.011 mmol, 0.05 equiv.) and5-bromo-1-methyl-3-(trifluoromethyl)pyrazole (102 mg, 0.446 mmol, 2equiv.) were loaded into a microwave reactor vial (2-5 mL), the vial wassealed and flushed with nitrogen (3×), 1,4-Dioxane (1.5 mL) was addedvia syringe and the reaction mixture was stirred at 110° C. in themicrowave reactor for 10 h. The resulting mixture was cooled down to RT,solution of Xanthphos (19 mg, 0.033 mmol, 0.15 equiv.) and Pd₂(dba)₃ (10mg, 0.011 mmol, 0.05 equiv.) in 1,4 dioxane (1 mL) was added, and thereaction mixture was stirred at 130° C. in the microwave reactor forfurther 10 h. The resulting suspension was cooled to RT, quenched withwater and extracted with DCM (3×). The combined organic layer was driedover Na₂SO₄ and concentrated under reduced pressure. The resultingresidue was purified by flash chromatography (gradient 0% to 16% MeOH inDCM) to yield 41 mg (42%) ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3319). ¹H NMR (600 MHz, DMSO) δ 7.71 (s, 1H), 7.41 (q, 1H),7.21-7.12 (m, 2H), 7.09 (td, 1H), 6.63 (s, 1H), 3.75 (s, 2H), 3.55 (s,2H), 2.42-2.27 (m, 2H), 1.99-1.89 (m, 8H), 1.88-1.73 (m, 2H), 1.56-1.49(m, 2H). Mass: m/z 440.2 (M+H)⁺.

Synthesis of SC_3340:CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide

Step 1:CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4]decan-3-yl)pyridin-4-yl)acetonitrile

In analogy to the method described for SC_3097 step 2CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)was reacted with (3-bromo-pyridin-4-yl)-acetonitrile to be convertedintoCIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile.

Step 2:CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide(SC_3340)

To a solution ofCIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile(600 mg, 1.54 mmol, 1.0 equiv.) in EtOH (50 ml) was added NaOH (247 mg,6.16 mmol, 4.0 equiv.). The reaction mixture was stirred at reflux for16 h and then concentrated under reduced pressure. The resulting residuewas purified by column chromatography (neutral alumina; 4% MeOH in DCM)and finally by preparative HPLC (column: Gemini NX-C18 (50×4.6), 31 μmdiluent: DMSO, mobile phase: gradient 0.05% HCOOH in water/ACN flowrate: 1 ml/min) to yieldCIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide(SC_3340) (40 mg, 0,098 mmol, 4% yield after two steps) as an off whitesolid. ¹HNMR (DMSO. 400 MHz) δ 8.40 (s, 1H), 8.32 (d, 1H, J=4.92 Hz),7.49 (s, 1H), 7.36-7.24 (m, 7H), 6.99 (s, 1H), 3.49-3.46 (m, 4H), 2.32(bs, 2H), 1.94-1.77 (m, 10H), 1.52 (bs, 2H). Mass: m/z 408.2 (M+H)⁺.

Synthesis of SC_3352:CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

In analogy to the method described for SC_3103CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)was reacted with7-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzooxazol-2-one(prepared from 7-bromobenzo[d]oxazol-2(3H)-one andtrimethylsilylethoxymethylchloride following a standard procedure) to beconverted intoCIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one.Mass: m/z 537.2 (M+H)⁺.

Step 2:CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3352)

To a solution ofCIS-7-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-3H-benzooxazol-2-one(350 mg, 0.65 mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added 4M HCl indioxane (6 mL) dropwise at 0° C. The reaction mixture was stirred at RTfor 48 h and then concentrated under reduced pressure. The residue wastaken in DCM (200 mL) and washed with sat. aq. NaHCO₃ (100 mL). Organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure toget the crude product which was purified by column chromatography(neutral alumina, 2% MeOH/DCM) to yieldCIS-7-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-3H-benzooxazol-2-one(SC_3352) (85 mg, 0.21 mmol, 32%) as an off white solid. ¹HNMR (DMSO-d6,400 MHz at 100° C.), δ (ppm)=11.19 (bs, 1H), 7.37-7.23 (m, 6H), 7.14 (s,1H), 7.04 (t, 1H, J=8.06), 6.76 (d, 1H, J=7.68 Hz), 3.69 (s, 2H),2.38-2.26 (m, 2H), 2.08-1.76 (m, 10H), 1.56-1.51 (m, 2H). Mass: m/z407.1 (M+H)⁺.

Synthesis of SC_3354:CIS-4-(5-(8-dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzamidetrifluoroacetate salt

3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT 989) (200 mg, 0.52 mmol, 1 equiv.),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (129 mg, 0.52mmol, 1 equiv.), Pd₂(dba)₃ (95 mg, 0.10 mmol, 0.2 equiv.),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (99 mg,0.21 mmol, 0.4 equiv.) were loaded into microwave reactor vessel andflushed with nitrogen (2×). Anhydrous 1,4-dioxane (9 mL) and sodiumcarbonate (213 mg, 2.07 mmol, 4 equiv.) were sequentially added. Thereaction mixture was stirred 8 h at 120° C. in the microwave reactor andthen concentrated under reduced pressure. The residue was suspended inEtOAc/water (1/1, v/v) and filtered through a glass filter. The solidresidue was dissolved in MeOH/DCM/TFA, filtered through Celite pad andthe filtrate was concentrated under reduced pressure to give 75 mg (25%)ofCIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzamidetrifluoroacetate salt (SC_3354). ¹H NMR (600 MHz, DMSO) δ 9.05 (s, 2H),8.42 (s, 1H), 8.34 (d, 2H), 8.03 (s, 1H), 7.98 (d, 2H), 7.74-7.65 (m,2H), 7.58 (t, 2H), 7.56-7.52 (m, 1H), 7.40 (s, 1H), 3.58 (s, 2H), 2.70(d, 2H), 2.60 (s, 6H), 2.25 (t, 2H), 1.91 (d, 2H), 1.39 (t, 2H). Mass:m/z 471.3 (M+H)⁺.

Synthesis of SC_3357:CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for SC_3103CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)was reacted with 3-bromo-1-(toluene-4-sulfonyl)-1H-indole to beconverted intoCIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3-diazaspiro[4.5]decan-2-one.Mass: m/z 543.1 (M+H)⁺.

Step 2:CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_3357)

To a solution of8-dimethylamino-8-phenyl-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-1,3-diaza-spiro[4.5]decan-2-one(275 mg, 0.51 mmol, 1.0 eq.) in EtOH (24 mL) was added 10N aq. NaOH (1.2mL) at RT. The reaction mixture was heated to reflux for 1.5 h. thenconcentrated, diluted with water (50 mL) and extracted with EtOAc (150mL). Organic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (neutralalumina; 2% MeOH/DCM) to affordCIS-8-dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(SC_3357) (130 mg, 0.33 mmol, 65%) as light brown solid. ¹H NMR(DMSO-d6, 400 MHz at 100° C.), δ (ppm)=10.55 (bs, 1H), 7.62-7.60 (d, 1H,J=7.96 Hz), 7.37-7.23 (m, 7H), 7.04 (t, 1H, J=7.48 Hz), 6.92 (t, 1H,J=7.44 Hz), 6.71 (bs, 1H), 3.61 (s, 2H), 2.38-2.33 (m, 2H), 2.04-1.82(m, 10H), 1.59-1.54 (m, 2H). Mass: m/z 389.3 (M+H)⁺.

Synthesis of SC_3379:CIS-3-(1-acetyl-1H-indol-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a solution of8-dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(SC_3357) (150 mg, 0.38 mmol, 1.0 eq.) in DCM (6 mL) were added NaOH (39mg, 0.96 mmol, 2.5 eq.) and Bu₄NHSO₄ (129 mg, 0.38 mmol, 1.0 eq.) at 0°C. and the reaction mixture was stirred for 30 min followed by additionof acetyl chloride (54 μl, 0.76 mmol, 2.0 eq.). The reaction mixture wasstirred at RT for 16 h. then diluted with DCM (150 ml) and washed withwater (50 mL) and brine (50 mL). Organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (neutral alumina; 1% MeOH/DCM) followed by prep HPLC toafford3-(1-acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(SC_3379) as off white solid. Note: Two batches of same reactions weredone and yield was calculated accordingly. Yield: 13% (45 mg, 0.1 mmol).1HNMR (DMSO-d6, 400 MHz at 100° C.), S (ppm)=8.34-8.32 (d, 1H, J=7.88Hz), 7.90 (d, 1H, J=7.36 Hz), 7.67 (s, 1H), 7.37-7.10 (m, 8H), 3.71 (s,2H), 2.57 (s, 3H), 2.38-2.32 (m, 2H), 2.04-1.88 (m, 10H), 1.61-1.59 (m,2H). Mass: in/z 431.2 (M+H)⁺.

Synthesis of SC_3388:CIS-8-(dimethylamino)-8-(3-hydroxyphenyl)-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one

CIS-8-(dimethylamino)-8-(3-methyloxyphenyl)-3-[4-ethyl-6-(trifluoromethyl)-3-pyridyl]-1,3-diazaspiro[4.5]decan-2-one(SC_3368) (42 mg, 0.091 mmol) was dissolved in DCM (2 mL) and thesolution was cooled to 0° C. Born tribromide (1 M sot, in DCM, 4 equiv.,0.36 mmol, 0.36 mil) was added in one portion. The reaction mixture wasallowed to stir at RT overnight, then quenched with methanol and dilutedwith water. The resulting mixture was extracted with DCM (2×), thecombined organic phases were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel (eluent gradient DCM/EtOH) to yield 16 mg (39%) ofCIS-8-(dimethylamino)-8-(3-hydroxyphenyl)-3-(4-methyl-6-(trifluormethyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_3388). ¹H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 7.80 (s, 1H), 7.52 (s,1H), 7.14 (t, 1H), 6.77 (d, 1H), 6.74 (s, 1H), 6.66 (dd, 1H), 3.61 (s,2H), 2.32 (s, 3H), 2.31-2.19 (m, 2H), 2.01-1.89 (m, 8H), 1.88-1.70 (m,2H), 1.54 (t, 2H). Mass: m/z 449.2 (M+H)⁺.

Synthesis of SC_3396:CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4S]decan-3-yl)indolin-2-one

Step 1:CIS4-(8-(dimethylamino)-2-oxo-4-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indoline-2,3-dione

In analogy to the method described for SC_3242CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)was reacted with 4-bromo-1-(4-methoxy-benzyl)-1H-indole-2,3-dione to beconverted intoCIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indoline-2,3-dione.Mass: m/z 539.2 (M+H)⁺.

Step 2:CIS-4-(8-(dimethylamino)-2-oxo-4-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indolin-2-one

To a solution ofCIS-4-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-1-(4-methoxy-benzyl)-1H-indole-2,3-dione(600 mg, 1.11 mmol, 1.0 eq) in EtOH (9 mL) was added hydrazine hydrate(9 mL) at RT. The reaction mixture was stirred at reflux for 16 h, thenconcentrated, diluted with water (50 mL) and extracted with EtOAc (200mL). Organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography (neutral alumina, 0.5% MeOH/DCM) to afford8-dimethylamino-3-[1-(4-methoxy-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(275 mg, 0.52 mmol, 47%) as a brown solid. Mass: m/z 525.2 (M+H)⁺.

Step 3:CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)indolin-2-one(SC_3396)

A solution of CIS-8-dimethylamino-3-[1(4-methoxy-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(275 mg, 0.52 mmol, 1.0 eq.) in TFA (4 mL) was stirred at 90° C. in asealed tube for 16 h. The reaction mixture was cooled to RT,concentrated under reduced pressure, diluted with water (50 mL),basified with sat. aq. NaHCO₃ and extracted with EtOAc (200 mL). Theorganic phase was washed with brine (50 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The resulting residue waspurified by column chromatography (neutral alumina, 5% McOH in DCM) toaffordCIS-8-dimethylamino-3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(SC_3396) (60 mg, 0.14 mmol, 28%) as an off-white solid. ¹H NMR(DMSO-d6, 400 MHz, 100° C.): δ (ppm)=9.98 (bs, 1H), 7.36-7.22 (m, 5H),7.09 (t, 1H, J=7.94 Hz), 6.95-6.88 (m, 2H), 6.59 (d, 1H, J=7.52 Hz),3.57 (s, 2H), 3.49 (s, 2H), 2.36-2.31 (m, 2H), 2.03 (s, 6H), 1.97-1.85(m, 4H), 1.55-1.51 (m, 2H). Mass: m/z 405.3 (M+H)⁺.

The following compounds were prepared in analogy and by combiningpreviously described methods:

in analogy to m/z Example Chemical Name Reactant I Reactant II method[M + H]⁺ SC_3001cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9875-bromopyrimidine-2- SC-3022 445.3diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile carbonitrileSC_3002 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-INT-987 5-bromopyrazine-2-carbonitrile SC-3022 445.3diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile SC_3003cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9875-bromo-4-methoxypyrimidine- SC-3022 475.3diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile2-carbonitrile SC_3004cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- INT-9805-bromopyrimidine-2- SC-3022 435.2diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile carbonitrileSC_3005 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-SC_3001 — SC_3016 463.3diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3006cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9875-bromo-2-(methylthio)- SC-3022 (step 523.2diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrilepyrimidine-4-carbonitrile 1); SC_3008 (step 2) SC_3007cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3- SC_3004 —SC_3045 421.2 diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrileSC_3008 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-INT-987 2-iodo-5- SC-3022 (step 521.3diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile(methylthio)benzonitrile (step 1) 1); SC_3008 (step 2) SC_3009cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- SC_3090— SC_3016 461.3 diazaspiro[4.5]decan-3-yl]-benzamide SC_3010cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- SC_3072— SC_3016 461.3 diazaspiro[4.5]decan-3-yl]-benzamide SC_3011cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-SC_3013 — SC_3016 479.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amideSC_3012 cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-SC_3003 — SC_3045 461.3diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3013cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-INT-600 — SC_3013 461.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3014cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9872-chloropyrimidine-5- SC_3014 445.3diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile carbonitrileSC_3015cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-INT-976 5-bromo-2-methoxypyrimidine SC_3013 466.3pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (step 1);1-(tert-butyldimethyl- silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3016cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- SC_3014— SC_3016 463.3 diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acidamide SC_3017cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- SC_3081methanamine SC_3028 475.3 diazaspiro[4.5]decan-3-yl]-N-methyl-benzamideSC_3018 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3- INT-6001-bromopropane SC_3013 419.2diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile SC_3019cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT-6001-bromo-3-methoxypropane SC-3013 449.3diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3020cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-INT-600 (bromomethyl)cyclopropane SC-3013 431.2diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3021cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- SC_3081ammonia SC-3028 461.3 diazaspiro[4.5]decan-3-yl]-benzamide SC_3022cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2- INT-9875-bromo-2- SC_3022 488.3(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one(trifluoromethyl)pyrimidine SC_3023cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-SC_3015 — SC_3023 452.3pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3024cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3- INT-6001-bromo-2-methylpropane SC_3013 433.3diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3025cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3- INT-600(3-bromopropoxy)(tert- SC-3025 421.2diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrilebutyl)dimethylsilane SC_3026cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- SC_3078 —SC_3045 444.3diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3027cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-SC_3075 — SC_3045 436.3 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3028cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- SC_3081— SC_3028 489.3 diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamideSC_3029 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-SC_3081 — SC_3028 533.3diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide SC_3030cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- SC_3008 —SC_3045 507.2 diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrileSC_3031 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfonyl-4-SC_3084 — SC_3031 550.2(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3032 cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-SC_3089 — SC_3032 579.3diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide SC_3033cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-INT-797 4-bromobenzonitrile (step 1); SC_3013 457.31,3-diazaspiro[4.5]decan-3-yl]-benzonitrile (bromomethyl)cyclobutane(step 2) SC_3034cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2- INT-7975-bromo-2- SC-3013 502.3(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one(trifluoromethyl)pyrimidine (step 1); (bromomethyl)cyclobutane (step 2)SC_3035cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-INT-797 5-bromopyrimidine-2- SC_3013 459.31,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile carbonitrile(step 1); (bromomethyl)cyclobutane (step 2) SC_3036cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8- INT-9825-bromopyrimidine-2- SC_3022 459.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrilecarbonitrile SC_3037cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-INT-978 5-bromopyrimidine-2- SC_3065 462.31,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide carbonitrileSC_3038 cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2- SC_3022 —SC_3038 474.2(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3039cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-oxo-INT-601 1-bromo-4-methoxybutane SC_3064 481.31,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3040cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT-9795-bromo-4-methoxypyrimidine- SC_3022 479.3diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile2-carbonitrile SC_3041cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8- INT_600(1-cyanocyclobutyl)methyl 4- SC_3013 470.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrilemethylbenzenesulfonate SC_3042cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-INT-601 (bromomethyl)cyclobutane SC_3064 549.38-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3043cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3- SC_3019 —SC_3043 435.2 diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboniltrileSC_3044 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3-INT_600 iodomethane SC_3013 409.2diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3045cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8- SC_3040 —SC_3045 465.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3046cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- INT-9804-bromopyrimidine-2- SC_3022 435.2diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile carbonitrileSC_3047 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-INT-980 5-bromo-4-methoxypyrimidine- SC_3022 465.3diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile2-carbonitrile SC_3048cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9874-bromopyrimidine-2- SC_3022 445.3diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile carbonitrileSC_3049 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6-methylsulfanyl-INT-987 4-bromo-6-(methylthio)- SC_3022 466.3pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one pyrimidineSC_3050cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-SC_3022 4-bromopyrimidine-2- SC_3022 462.31,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide carbonitrileSC_3051 cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-INT-987 6-bromopyrimidine-4- SC_3022 445.3diazaspiro[4.5]decan-3-yl]-pyrimidine-4-carbonitrile carbonitrileSC_3052cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-INT-987 bromobenzene SC_3022 435.3 yl)-N,N-dimethyl-acetamide SC_3053cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3- INT-987bromobenzene SC_3022 418.3 diazaspiro[4.5]decan-2-one SC_3054cis-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- INT-9805-chloropyrimidine-2- SC_3022 435.2diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile carbonitrileSC_3055 cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-INT-980 bromobenzene SC_3022 408.3 diazaspiro[4.5]decan-2-one SC_3056cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- INT-9805-bromo-4-methylpicolinonitrile SC_3022 448.3diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3057cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3- SC_3052 —SC_3045 421.3 diazaspiro[4.5]decan-1-yl)-acetamide SC_3058cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-SC_3041 — SC_3058 456.21,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3059cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-oxo-INT-797 5-bromopyrimidine-2-carbo- SC_3013 484.38-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrilenitrile (step 1); 1-(bromo- methyl)cyclobutanecarbonitrile (step 2)SC_3060CIS-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-INT-987 4-bromobenzonitrile (step 1); (1- SC_3013 459.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile (tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzene- sulfonate (2step) SC_3061cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-INT-987 3-bromobenzonitrile (step 1); (1- SC_3013 459.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile (tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzene- sulfonate (step2) SC_3063cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8 INT-9875-bromopicolinonitrile (step 1); SC_3013 469.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile1-(bromomethyl)cyclo- butanecarbonitrile (step 2) SC_3064cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-INT-600 2-bromo-N-propylacetamide SC_3064 476.31,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_3065cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-INT-986 5-bromo-4-methoxypyrimidine- SC_3065 489.31,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile2-carbonitrile SC_3066cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- SC_3080 —SC_3066 459.3 diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3067cis-5-[8-Diamethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- INT-9795-bromo-6- SC_3022 478.3diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrilemethoxypicolinonitrile SC_3068cis-4-[8-Diamethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-SC_3060 — SC_3016 477.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamideSC_3069cis-5-[8-Diamethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-INT-976 5-bromopicolinonitrile (step 1); SC_3013 460.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile1-(tert-butyldimethylsilyloxy)- cyclobutyl)methyl 4-methyl-benzene-sulfonate (step 2) SC_3070cis-5-[8-Diamethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-INT-976 5-bromopicolinonitrile (step 1); SC_3013 562.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-1-(tert-butyldimethylsilyloxy)- methyl]-pyridine-2-carboxylic acid amidecyclobutyl)methyl 4-methyl- benzene-sulfonate (step 2) SC_3071cis-2-[8-Diamethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-INT-976 2-bromobenzonitrile (step 1); 1- SC_3013 459.3phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile(tert-butyldimethylsilyloxy)- cyclobutyl)methyl 4-methyl-benzene-sulfonate (step 2) SC_3072cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9873-iodobenzonitrile SC_3022 443.3 diazaspiro[4.5]decan-3-yl]-benzonitrileSC_3073 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2- INT-9875-bromo-2- SC_3022 488.3(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one(trifluoromethyl)pyrimidine SC_3074cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-987methyl 5-bromo-4-methyl- SC_3022 491.3diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylic acid methylpicolinate ester SC_3075cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-INT-987 2-bromo-5-methoxypyrazine SC_3022 450.3yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3076cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrazin-5-INT-987 5-bromo-2-methoxypyrimidine SC_3022 450.3yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3077cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9874-iodobenzonitrile SC_3022 443.3 diazaspiro[4.5]decan-3-yl]-benzonitrileSC_3078 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-INT-987 5-bromo-4-methylpicolinonitrile SC_3022 458.3diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3079cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-INT-987 2-bromo-5-fluoropyrimidine SC_3022 438.38-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3080cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9874-bromo-3-methoxybenzonitrile SC_3022 473.3diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3081cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-987methyl 4-iodobenzoate SC_3022 476.3 diazaspiro[4.5]decan-3-yl]-benzoicacid methyl ester SC_3082cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-1-INT-987 4-iodo-2-(pyrrolidin-1- SC_3022 489.3yl)-pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one yl)-pyrimidineSC_3083cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyrrolidin-2-yl-INT-987 2-(5-bromothiophen-2- SC_3022 501.3thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one y-l)pyridine SC_3084cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4- INT-9871-bromo-2-(methylsulfonyl)-4- SC_3022 564.2(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(trifluoromethyl)benzene SC_3085cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6- INT-9875-bromo-2- SC_3022 487.3(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one(trifluoromethyl)pyridine SC_3086cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8-dimethylamino-INT-987 1-bromo-2,4-dimethoxybenzene SC_3022 478.38-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3087cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT_9872-iodo-4-(methylthio)- SC_3022/ 521.3diazaspiro[4.5]decan-3-yl]-4-methylsulfonyl-benzonitrile benzonitrile(SC_3022) SC_3008 SC_3088cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9875-bromo-2-fluorobenzonitrile SC_3022 461.3diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile SC_3089cis-4-[1-(Cyclobulyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9874-bromo-N,N-dimethyl-3- SC_3022 593.3diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-(trifluoromethyl)benzenesulfonamide benzenesulfonic acid amide SC_3090cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9872-bromobenzonitrile SC_3022 443.3 diazaspiro[4.5]decan-3-yl-benzonitrileSC_3091cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2-INT-987 6-bromo-2-methylimidazo[1,2- SC_3022 473.3a]pyrazin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one a]pyrazineSC_3092 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-INT-987 (4-iodophenyl)(methyl)sulfane SC_3022/ 496.3phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3008 SC_3093cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- INT-9872-bromo-5-methoxybenzonitrile SC_3022 473.3diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile SC_3094cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3- INT-987bromobenzene SC_3022 418.3 diazaspiro[4.5]decan-2-one SC_3096cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-pyrazin-2-yl-INT-987 2-bromopyrazine SC_3022 420.3 1,3-diazaspiro[4.5]decan-2-one inanalogy to m/z Example Chemical name Reactant I Reactant II method ¹HNMR data (M + H)⁺ SC_3098 cis-8-Dimethylamino-1-[(1-hydroxy- INT-7995-bromo-2-(4- SC_3097 1H NMR (DMSO-d6): δ 8.56 (s, 2H), 7.36-7.35 (m,534.4 cyclobutyl)-methyl]-3-[2-(4-methyl- methylpiperazin-1- 4H),7.27-7.24 (m, 1H), 5.52 (s, 1H), 3.71 (s, 2H),piperazin-1-yl)-pyrimidin-5-yl]-8- yl)pyrimidine 3.64 (m, 4H), 3.21 (s,2H), 2.69-2.67 (m, 2H), phenyl-1,3-diazaspiro[4.5]decan-2-one 2.32 (m,4H), 2.19-2.11 (m, 7H), 1.98 (s, 6H), 1.92-1.86 (m, 2H), 1.66-1.64 (m,1H), 1.52-1.42 (m, 5H). SC_3101 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-SC_3098 SC_3099 1H NMR (DMSO-d6): δ 8.58 (s, 2H), 7.48 (d, 2H), 520.48-methylamino-3-[2-(4-methyl- 7.32 (t, 2H), 7.19 (t, 1H), 5.61 (s, 1H),3.75 (s, 2H), piperazin-1-yl)-pyrimidin-5-yl]-8- 3.66-3.64 (m, 4H), 3.30(s, 2H), 2.35-2.32 (m, 4H), phenyl-1,3-diazaspiro[4.5]decan-2-one2.25-2.19 (m, 5H), 2.12-2.07 (m, 2H), 1.90-1.88 (m, 7H), 1.79-1.73 (m,2H), 1.65-1.63 (m, 1H), 1.50-1.44 (m, 3H) SC_3102cis-1-[(1-Hydroxy-cyclobutyl)-methyl]- SC_3100 SC_3099 1H NMR (DMSO-d6):δ 9.51 (br s, 2H), 9.15 (br s, 506.38-methylamino-8-phenyl-3-(2-piperazin- 2H), 8.65 (s, 2H), 7.69-7.68 (m,2H), 7.50-7.41 (m, 1-yl-pyrimidin-5-yl)-1,3- 3H), 3.88-3.86 (m, 4H),3.79 (m, 2H), 3.65 (m, 2H), diazaspiro[4.5]decan-2-one 3.16-3.13 (m,4H), 2.64-2.62 (m, 2H), dihydrochloride 2.38-2.33 (m, 2H), 2.16-2.04 (m,7H), 1.90-1.84 (m, 2H), 1.76-1.70 (m, 3H), 1.60-1.58 (m, 1H). SC_3104cis-1-(Cyclobutyl-methyl)-8- SC_3103 SC_3099 1H NMR (DMSO-d6): δ 8.59(s, 1H), 7.81 (s, 1H), 487.3 methylamino-3-[4-methyl-6- 7.44 (d, 2H),7.30 (t, 2H), 7.17 (t, 1H), 3.76 (s, 2H),(trifluoromethyl)-pyridin-3-yl]-8-phenyl- 3.21 (d, 2H), 2.61-2.57 (m,1H), 2.32 (s, 3H), 1,3-diazaspiro[4.5]decan-2-one 2.29-2.17 (m, 3H),2.03-1.97 (m, 2H), 1.91-1.88 (m, 5H), 1.84-1.67 (m, 6H), 1.51-1.48 (m,2H). SC_3106 cis-1-(Cyclopropyl-methyl)-8- SC_3105 SC_3099 1H NMR(DMSO-d6): δ 7.90-7.88 (d, 2H), 468.2 methylamino-3-(4-methylsulfonyl-7.82-7.80 (d, 2H), 7.50-7.48 (d, 2H), 7.35-7.32 (m, 2H),phenyl)-8-phenyl-1,3- 7.22-7.19 (m, 1H), 3.80 (s, 2H), 3.14-3.10 (m,5H), diazaspiro[4.5]decan-2-one 2.29-2.23 (m, 3H), 1.91-1.79 (m, 7H),1.42-1.39 (m, 2H), 1.05-1.04 (m, 1H), 0.50-0.47 (m, 2H), 0.34-0.32 (m,2H). SC_3107 cis-1-(Cyclopropyl-methyl)-8- INT-983 1-bromo-2-fluoro-4-SC3103 (step 1), 1H NMR (DMSO-d6): δ 7.85 (t, 1H), 7.79-7.76 (m, 500.2dimethylamino-3-(2-fluoro-4- (methylsulfonyl)benzene SC_3105 (step 2)1H), 7.72-7.69 (m, 1H), 7.37-7.33 (m, 4H),methylsulfonyl-phenyl)-8-phenyl-1,3- (step 1), 7.27-7.24 (m, 1H), 3.81(s, 2H), 3.24 (s, 3H), 3.07 (d, diazaspiro[4.5]decan-2-one(Bromomethyl)cylopropane 2H), 2.71-2.68 (m, 2H), 2.28-2.22 (m, 2H), 1.99(s, (step 2) 6H), 1.53-1.42 (m, 4H), 1.00-0.99 (m, 1H), 0.53-0.49 (m,2H), 0.34-0.30 (m, 2H). SC_3108 cis-2-[8 -Dimethylamino-1-[(1-hydroxy-SC_3071 SC_3016 1H NMR (600 MHz, DMSO) δ 7.59-7.55 (s, 1H), 477.3cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- 7.47-7.39 (m, 2H), 7.39-7.31 (m,5H), diazaspiro[4.5]decan-3-yl]-benzamide; 7.30-7.21 (m, 3H), 3.77-3.73(s, 2H), 3.21-3.17 (s, formic acid 1H), 2.72-2.66 (d, 2H), 2.17-2.09 (m,5H), 2.02-1.99 (s, 6H), 1.95-1.86 (m, 2H), 1.71-1.60 (m, 3H), 1.49-1.37(m, 3H) SC_3109 cis-2-[8-Dimethylamino-1-[2-(1- INT9882-bromobenzonitrile SC_3097 (step 1), 1H NMR (600 MHz, DMSO) δ 7.52-7.48(s, 1H), 505.3 methoxy-cyclobutyl)-ethyl]-2-oxo-8- SC_3109 (step 2)7.47-7.31 (m, 7H), 7.29-7.23 (m, 1H),phenyl-1,3-diazaspiro[4.5]decan-3-yl]- 7.25-7.22 (s, 1H), 7.24-7.18 (m,1H), 3.68-3.65 (s, benzamide 3H), 3.13-3.10 (s, 2H), 3.09-3.02 (m, 2H),2.71-2.65 (m, 2H), 2.21-2.12 (m, 2H), 2.09-1.99 (m, 2H), 2.02-1.98 (s,6H), 1.97-1.86 (m, 4H), 1.77-1.67 (m, 1H), 1.64-1.52 (m, 3H), 1.44-1.36(td, 2H). SC_3110 cis-8-Dimethylamino-1-[2-(1-methoxy- INT-9885-bromo2-methyl- SC_3103 1H NMR (600 MHz, DMSO) δ 8.94-8.90 (s, 2H),478.3 cyclobutyl)-ethyl]-3-(2-methyl- pyrimidine 7.41-7.34 (d, 4H),7.32-7.24 (ddd, 1H), pyrimidin-5-yl)-8-phenyl-1,3- 3.76-3.72 (s, 2H),3.15-3.08 (m, 5H), 2.72-2.65 (m, diazaspiro[4.5]decan-2-one 2H),2.57-2.52 (s, 3H), 2.25-2.16 (m, 2H), 2.11-2.02 (m, 2H), 2.03-1.99 (s,6H), 1.99-1.86 (m, 4H), 1.78-1.68 (tq, 1H), 1.65-1.51 (m, 3H), 1.50-1.44(d, 2H). SC_3111 cis-5-[1-[(1-Hydroxy-cyclobutyl)- INT-799 5-bromo-2-SC_3103 (step 1), 1H NMR (600 MHz, DMSO) δ 9.24-9.20 (s, 2H), 447.3methyl]-8-methylamino-2-oxo-8-phenyl- cyanopyrimide SC_3099 (step 2)7.53-7.48 (m, 2H), 7.37-7.31 (t, 2H), 1,3-diazaspiro[4.5]decan-3-yl]-7.25-7.19 (t, 1H), 3.93-3.89 (s, 2H), 3.42-3.36 (m, 2H),pyrimidine-2-carbonitrile 2.35-2.26 (td, 2H), 2.18-2.10 (tt, 2H),2.09-2.04 (s, 1H), 1.97-1.88 (m, 2H), 1.93-1.90 (s, 6H), 1.86-1.77 (td,2H), 1.72-1.62 (s, 1H), 1.59-1.54 (d, 1H), 1.48-1.43 (d, 2H). SC_3113cis-4-[1-[(1-Hydroxy-cyclobutyl)- INT-976 1-bromo-4-cyano-2- SC_31121HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.54 (s, 475.3methyl]-8-methylamino-2-oxo-8-phenyl- methoxybenzene (step 1) 1H), 7.50(d, 1H, J = 8.16 Hz), 7.46-7.39 (m, 3H),1,3-diazaspiro[4.5]decan-3-yl]-3- 7.30 (t, 2H, J = 7.48 Hz), 7.18 (t,1H, J = 7.16 Hz), methoxy-benzonitrile 5.59 (s, 1H), 3.85 (s, 3H), 3.73(s, 2H), 3.30 (s, 2H, merged with DMSO-water), 2.32-2.08 (m, 4H),1.91-1.87 (m, 7H), 1.68-1.47 (m, 6H). SC_3114cis-4-[8-Ethylamino-1-[(1-hydroxy- INT-1008 4-Bromo-3-methoxy- SC_3112(step 1, 1HNMR (DMSO-d6, 400 MHz), δ ppm) = 7.54 (s, 489.1cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- benzonitile (step 1) step 2)1H), 7.51-7.45 (m, 3H), 7.40 (d, 1H, J = 8.24 Hz),diazaspiro[4.5]decan-3-yl]-3-methoxy- 7.29 (t, 2H, J = 7.58 Hz), 7.17(t, 1H J = 7.12 (Hz), benzonitrile 5.60 (s, 1H), 3.85 (s, 3H), 3.73 (s,2H), 3.21 (s, 2H, merged with DMSO-H2O), 2.32-2.27 (m, 2H), 2.08 (bs,5H), 1.96-1.87 (m, 4H), 1.68-1.46 (m, 6H), 0.97 (t, 3H, J = 4.0 Hz).SC_3115 cis-2-[8-Ethylamino-1-[(1-hydroxy- INT-1008 2-bromo-benzonitrileSC_3112 (step 1, 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.82 (d, 458.9cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- (step 1) step 2) 1H, J = 7.56Hz), 7.71 (t, 1H, J = 6.98 Hz), diazaspiro[4.5]decan-3-yl]-benzonitrile7.53-7.47 (m, 3H), 7.37-7.27 (m, 3H), 7.19-7.17 (m, 1H), 5.55 (s, 1H),3.87 (s, 2H), 3.38 (s, 2H), 2.36-2.32 (m, 2H), 2.10 (bs, 4H), 1.94-1.86(m. 4H), 1.75-1.48 (6H), 0.98 (bs, 3H). SC_3116cis-5-[1-[(1-Hydroxy-cyclobutyl)- INT-799 5-bromo-4-methoxy- SC_3103(step 1), 1HNMR (DMSO-d6, 400 MHz, at 100° C.), δ 477.2methyl]-8-methylamino-2-oxo-8-phenyl- pyrimidine-2-carbonitrile SC_3099(step 2) (ppm) = 8.79 (s, 1H), 7.46 (d, 2H, J = 7.84 Hz),1,3-diazaspiro[4.5]decan-3-yl]-4- (step 1) 7.32 (t, 2H, J = 7.12 Hz),7.19 (t, 1H, J = 7.28 Hz), methoxy-pyrimidine-2-carbonitrile 5.09 (bs,1H), 4.05 (s, 3H), 3.85 (s, 2H), 3.38 (s, 2H), 2.31-2.15 (m, 4H), 1.98(m, 7H), 1.74-1.51 (m, 6H). SC_3117cis-2-[8-Dimethylamino-1-(oxetan-3-yl- SC_3274 toluene-4-sulfonic acidSC_3105 (step 1), 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.52 (s, 463.4methyl)-2-oxo-8-phenyl-1,3- oxetan-3-ylmethyl ester SC_3016 (step 2)1H), 7.43-7.33 (m, 6H), 7.30-7.17 (m, 4H),diazaspiro[4.5]decan-3-yl]-benzamide (step 1) 4.63 (t, 2H, J = 6.9 Hz),4.39 (t, 2H, J = 6.08 Hz), 3.64 (s, 2H), 3.38 (d, 2H, J = 7.32 Hz),3.21-3.15 (m, 1H), 2.70-2.66 (m, 2H), 2.08-1.98 (m, 8H), 1.54-1.35 (m,4H). SC_3118 cis-4-Methoxy-5-(8-methylamino-2-oxo- INT-9765-bromo-4-methoxy- SC_3103 (step 1), 1HNMR (DMSO-d6, 400 MHz), δ (ppm) =8.80 (s, 393.0 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile SC_3099 (step 2) 1H), 7.86 (bs, 1H), 7.43 (d,2H, J = 7.84 Hz), pyrimidine-2-carbonitrile (step 1) 7.32 (t, 2H, J =7.32 Hz), 7.21-7.18 (m, 1H), 4.02 (s, 3H), 3.83 (s, 2H), 2.07-2.00 (m,3H), 1.90-1.74 (m, 7H), 1.48 (d, 2H, J = 13.8 Hz). SC_3119cis-2-(8-Methylamino-2-oxo-8-phenyl- INT-976 2-bromo-benzonitrileSC_3103 (step 1), 1HNMR (DMSO-d6, 400 MHz) δ 7.51 (bs, 1H), 379.41,3-diazaspiro[4.5]decan-3-yl)- (step 1) SC_3099 (step 2), 7.43-7.37 (m,4H), 7.33-2.29 (m, 3H, J = 8.28 Hz), benzamide SC_3016 (step 3)7.22-7.16 (m, 3H), 6.93 (bs, 1H), 3.64 (s, 2H), 2.03-1.97 (m, 2H), 1.86(bs, 5H), 1.73-1.58 (m, 4H). SC_3121cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8- INT-976 5-bromo-2-cyclopropyl-SC_3103 1HNMR (600 MHz, DMSO) δ 8.80 (s, 2H), 392.3dimethylamino-8-phenyl-1,3- pyrimidine 7.67 (s, 1H), 7.41-7.32 (m, 4H),7.31-7.22 (ddt, 1H), diazaspiro[4.5]decan-2-one 3.60 (s, 2H), 2.42-2.36(m, 2H), 2.18-2.08 (m, 1H), 1.98-1.85 (m, 4H), 1.96 (s, 6H), 1.47 (s,2H), 0.98-0.91 (m, 2H), 0.93-0.86 (m, 2H). SC_3122cis-8-Dimethylamino-3-[4-methyl-6- INT-976 5-bromo-4-methyl-2- SC_31031H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 433.2(trifluoromethyl)-pyridin-3-yl]-8-phenyl- (trifluoromethyl)pyridine 7.79(s, 1H), 7.52 (s, 1H), 7.40-7.32 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one7.30-7.22 (tt, 1H), 3.61 (s, 2H), 2.39-2.30 (m, 5H), 1.96 (s, 6H),2.00-1.91 (m, 2H), 1.84 (s, 2H), 1.57-1.53 (s, 2H). SC_3123cis-8-Dimethylamino-3-(2- INT-976 1-bromo-2- SC_3103 1H NMR (600 MHz,DMSO) δ 7.98-7.92 (dd, 428.2 methylsulfonyl-phenyl)-8-phenyl-1,3-methylsulfonyl-benzene 1H), 7.81-7.74 (td, 1H), 7.61-7.54 (td, 1H),diazaspiro[4.5]decan-2-one 7.52-7.46 (m, 2H), 7.41-7.31 (m, 2H), 7.35(s, 2H), 7.29-7.22 (tt, 1H), 3.49 (s, 2H), 3.25 (s, 3H), 2.37 (s, 2H),1.99-1.96 (m, 1H), 1.98-1.94 (s, 6H), 1.95-1.91 (d, 1H), 1.83-1.79 (m,2H), 1.58-1.55 (s, 2H). SC_3124 cis-8-Dimethylamino-8-phenyl-3-(2-INT-989 Piperazine-2-one SC_3120 1H NMR (600 MHz, DMSO) δ 8.52 (s, 2H),436.3 piperazin-1-yl-pyrimidin-5-yl)-1,3- 7.41-7.31 (m, 5H), 3.59-3.54(m, 4H), 3.52 (s, 2H), diazaspiro[4.5]decan-2-one 2.76-2.70 (m, 4H),2.55 (s, 3H), 2.49-2.33 (m, 2H), 1.96 (s, 6H), 1.93-1.83 (m, 4H),1.51-1.43 (s, 2H). SC_3125 trans-2-(8-Ethylamino-2-oxo-8-phenyl- SC_3127SC_3016 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.56-7.20 (m, 393.11,3-diazaspiro[4.5]decan-3-yl)- 12H), 3.60 (s, 2H), 2.08-1.92 (m, 6H),benzamide 1.69 (bs, 2H), 1.56 (bs, 2H), 0.93 (t, 3H). SC_3126cis--2-(8-Ethylamino-2-oxo-8-phenyl- SC_3128 SC_3016 ¹HNMR (DMSO-d₆, 400MHz), δ (ppm) = 7.51-2.38 (m, 393.4 1,3-diazaspiro[4.5]decan-3-yl)- 5H),7.32-7.30 (m, 3H), 7.22-7.18 (m, benzamide 3H), 6.93 (s, 1H), 3.63 (s,2H), 2.07-1.98 (m, 4H), 1.86-1.72 (m, 4H), 1.60-1.57 (m, 2H), 0.93 (t,3H). SC_3127 cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3- INT-10092-bromo-benzonitrile SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.77(d, 375.1 diazaspiro[4.5]decan-3-yl)-benzonitrile 1H, J = 6.8 Hz),7.69-7.65 (m, 1H), 7.51 (d, 1H, J = 8.4 Hz), 7.44 (d, 2H, J = 7.6 Hz),7.39 (s, 1H), 7.34-7.28 (m, 3H), 7.17 (t, 1H, 7.2 Hz), 3.77 (s, 2H),2.10-2.04 (m, 4H), 1.91-1.88 (m, 2H), 1.80-1.74 (m, 3H), 1.61-1.58 (m,2H), 0.94 (t, 3H, J = 6.8 Hz). SC_3128cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3- INT-1008 2-bromo-benzonitrileSC_3103 ¹HNMR (DMSO-d₆, 400 MHz), δ (ppm) = 7.89 (bs, 375.1diazaspiro[4.5]decan-3-yl)-benzonitrile 1H), 7.79 (d, 1H, J = 7.6), 7.69(t, 1H, J = 7.6 Hz), 7.54-7.50 (m, 3H), 7.36-7.30 (m, 3H), 7.18 (t, 1H,J = 7.2 Hz), 3.73 (s, 2H), 2.08-1.92 (m, 7H), 1.71 (bs, 2H), 1.59 (bs,2H,), 0.93 (t, 3H, J = 6.4 Hz). SC_3131cis-3-[5-(8-Dimethylamino-2-oxo-8- SC_3129 SC_3016 1H NMR (600 MHz,DMSO) δ 9.11 (s, 2H), 471.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 8.79(t, 1H), 8.43 (dt, 1H), 8.09 (s, 1H), 7.94 (dt, 1H),pyrimidin-2-yl]-benzamide 7.84 (s, 1H), 7.56 (t, 1H), 7.41-7.35 (m, 4H),7.28 (ddd, 1H), 3.72 (s, 2H), 2.00-1.84 (m, 2H), 1.98 (s, 6H), 1.53 (s,2H). SC_3134 trans-4-(8-Ethylamino-2-oxo-8-phenyl- INT-10094-Bromo-3-methoxy- SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.71 (bs,405.3 1,3-diazaspiro[4.5]decan-3-yl)-3- benzonitrile 1H), 7.56-7.49 (m,4H), 7.37 (d, 1H, J = 6.6 Hz), methoxy-benzonitrile 7.31 (t, 2H, J =7.10 Hz), 7.19-7.17 (m, 1H), 3.87 (s, 3H), 3.62 (s, 2H), 2.06-1.90 (m,7H), 1.69-1.53 (m, 4H), 0.92 (t, 3H, J = 6.70 Hz). SC_3135cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3- INT-1008 4-Bromo-3-methoxy-SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.52-7.50 (m, 405.2diazaspiro[4.5]decan-3-yl)-3-methoxy- benzonitrile 2H), 7.44-7.43 (m,2H), 736 (d, 1H, J = 8.04 Hz), benzonitrile 7.30-7.19 (m, 4H), 3.83 (s,3H), 3.63 (s, 2H), 2.05-1.72 (m, 8H), 1.53-1.50 (m, 2H), 0.92 (t, 3H).SC_3136 cis-3-[2-(4-Acetyl-piperazin-1-yl)- SC_3124 acetyl chlorideSC_3130 478.3 pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3137cis-8-Dimethylamino-8-phenyl-3-(2- INT-989 pyridine-4-boronic acidSC_3129 1H NMR (600 MHz, DMSO) δ 9.16 (s, 2H), 429.2pyridin-4-yl-pyrimidin-5-yl)-1,3- 8.70 (d, 1H), 8.18 (s, 1H), 7.91 (s,1H), 7.42-7.35 (m, diazaspiro[4.5]decan-2-one 4H), 7.28 (tt, 1H), 3.73(s, 2H), 2.49-2.37 (m, 2H), 1.98 (s, 6H), 2.01-1.87 (m, 2H), 1.58-1.47(m, 2H). SC_3138 cis-8-Dimethylamino-8-phenyl-3-(2- INT-989pyridine-3-boronic acid SC_3129 1H NMR (600 MHz, DMSO) δ 9.43 (dd, 1H),429.2 pyridin-3-yl-pyrimidin-5-yl)-1,3- 9.13 (s, 2H), 8.65 (dd, 1H),8.58 (dt, 1H), 7.52 (ddd, 1H), diazaspiro[4.5]decan-2-one 7.42-7.36 (m,4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 1.98 (s, 6H), 2.02-1.89 (m, 4H),1.57-1.46 (m, 4H). SC_3139 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-INT-991 2-aminoethanol SC_3133 1H NMR (600 MHz, DMSO) δ 9.08 (s, 2H),439.3 1,3-diazaspiro[4.5]decan-3-yl)-N-(2- 8.59 (t, 1H), 7.94 (s, 1H),7.43-7.30 (m, 5H), hydroxy-ethyl)-pyrimidine-2-carboxylic 7.30-7.21 (m,1H), 3.72 (s, 2H), 3.51 (q, 2H), acid amide 2.49-2.37 (m, 2H), 2.00-1.90(m, 10H), 1.89-1.74 (m, 2H), 1.57-1.48 (m, 2H), 1.38-1.32 (m, 1H).SC_3141 cis-8-Dimethylamino-3-[2-morpholin-4- INT-976 4-[5-bromo-4-SC_3103 1H NMR (600 MHz, DMSO) δ 8.59 (d, 1H), 505.3yl-4-(trifluoromethyl)-pyrimidin-5-yl]-8- (trifluoromethyl)pyrimidin-7.39-7.35 (m, 5H), 7.27 (d, 1H), 3.73 (t, 4H), 3.67 (q,phenyl-1,3-diazaspiro[4.5]decan-2-one 2-yl]morpholine 4H), 3.28-3.22 (m,1H), 2.41-2.28 (m, 2H), 1.98 (s, 6H), 1.94-1.80 (m, 3H), 1.53-1.42 (m,2H). SC_3142 cis-4-[5-(8-Dimethylamino-2-oxo-8- INT-9894-cyanophenylboronic SC_3129 1H NMR (600 MHz, DMSO) δ 9.15 (s, 2H),453.2 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- acid 8.49-8.43 (m, 2H),7.99-7.92 (m, 2H), 7.89 (s, 1H), pyrimidin-2-yl]-benzonitrile 7.38 (m,4H), 7.28 (td, 1H), 3.73 (s, 2H), 2.48-2.35 (m, 1H), 2.03-1.90 (m, 10H),1.55-1.48 (m, 2H). SC_3143 cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-INT-1008 5-Bromo-4-methoxy- SC_3103 (DMSO-d6, 400 MHz), δ (ppm) = 8.79(s, 1H), 407.2 diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile 7.60 (s, 1H), 7.41 (d, 2H, J = 7.72 Hz), 7.28(t, 2H, pyrimidine-2-carbonitrile J = 7.54 Hz), 7.16 (t, 1H, J = 7.32Hz), 3.97 (s, 3H), 3.72 (s, 2H), 2.02 (bs, 4H), 1.90-1.69 (m, 5H),1.51-1.48 (m, 2H), 0.89 (t, 3H, J = 6.56 Hz). SC_3144trans-5-(8-Ethylamino-2-oxo-8-phenyl- INT-1009 5-Bromo-4-methoxy-SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 8.87 (s, 407.31,3-diazaspiro[4.5]decan-3-yl)-4- pyrimidine-2-carbonitrile 1H), 8.10(bs, 1H), 7.50 (d, 2H, J = 7.52 Hz), methoxy-pyrimidine-2-carbonitrile7.31 (t, 2H, J = 7.20 Hz), 7.18 (t, 1H, J = 6.88 Hz), 4.04 (s, 3H), 3.74(s, 2H), 2.07-1.95 (m, 6H), 1.70-1.54 (m, 4H), 0.93 (t, 3H, J = 6.62Hz). SC_3145 cis-8-Dimethylamino-3-[2-(morpholine- INT-991 morpholineSC_3133 1H NMR (600 MHz, DMSO) δ 9.04 (s, 2H), 478.34-carbonyl)-pyrimidin-5-yl]-8-phenyl- 7.88 (s, 1H), 7.42-7.30 (m, 5H),7.30-7.22 (m, 1H), 1,3-diazaspiro[4.5]decan-2-one 3.75-3.58 (m, 6H),3.51 (t, 2H), 3.20 (t, 2H), 2.50-2.33 (m, 2H), 1.99-1.90 (m, 8H),1.89-1.74 (m, 2H), 1.54-1.44 (m, 2H). SC_3147 cis-8-Dimethylamino-3-[2-INT-976 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 7.47 (d, 1H), 442.2(methylsulfonyl-methyl)-phenyl]-8- (methylsulfonylmethyl)benzene7.42-7.31 (m, 6H), 7.30-7.22 (m, 3H), 4.50 (s, 2H),phenyl-1,3-diazaspiro[4.5]decan-2-one 3.56 (s, 2H), 2.88 (s, 3H),2.42-2.28 (m, 2H), 2.07 (s, 2H), 1.98-1.90 (m, 8H), 1.89-1.69 (m, 2H),1.61-1.48 (d, 2H). SC_3148 cis-8-Dimethylamino-3-(4-methyl-2 INT-992morpholine SC_3120 1H NMR (600 MHz, DMSO) δ 8.14 (s, 1H), 451.3morpholin-4-yl-pyrimidin-5-yl)-8- 7.40-7.32 (m, 4H), 7.26 (td, 1H), 7.21(s, 1H), phenyl-1,3-diazaspiro[4.5]decan-2-one 3.69-3.60 (m, 8H), 3.38(s, 2H), 2.41-2.27 (m, 2H), 2.20 (s, 3H), 1.97 (s, 6H), 1.95-1.76 (m,4H), 1.54-1.45 (s, 2H). SC_3149 cis-8-Dimethylamino-3-[2-(1,1-dioxo-INT-989 thiomorpholine-1,1- SC_3120 1H NMR (600 MHz, DMSO) δ 8.63 (s,2H), 485.2 [1,4]thiazinan-4-yl)-pyrimidin-5-yl]-8- dioxide hydrochloride7.50 (br s, 1H), 7.41-7.33 (m, 4H), 7.27 (td, 1H),phenyl-1,3-diazaspiro[4.5]decan-2-one 4.17-4.12 (m, 4H), 3.55 (s, 2H),3.12-3.06 (m, 4H), 2.47-2.27 (m, 2H), 2.04-1.74 (m, 10H), 1.51-1.42 (m,2H). SC_3150 cis-8-Dimethylamino-3-(4-fluoro- INT-976 3-bromo-4-fluoro-SC_3103 1H NMR (600 MHz, DMSO) δ 8.70 (d, 1H), 369.2pyridin-3-yl-8-phenyl-1,3- pyridine 8.36 (dd, 1H), 7.54 (s, 1H), 7.36(td, 5H), 7.26 (s, 1H), diazaspiro[4.5]decan-2-one 3.61 (s, 2H),2.44-2.28 (m, 2H), 2.01-1.74 (m, 10H), 1.92 (d, 2H), 1.56-1.45 (m, 2H).SC_3151 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-9912-(methylamino)ethanol SC_3133 1H NMR (600 MHz, DMSO) δ 9.03 (d, 2H),453.2 1,3-diazaspiro[4.5]decan-3-yl)-N-(2- 7.86 (s, 1H), 7.40-7.23 (m,5H), 3.69 (s, 2H), 3.61 (q, hydroxy-ethyl)-N-methyl-pyrimidine-2- 1H),3.50 (t, 1H), 3.45 (d, 1H), 3.17 (t, 1H), 3.01 carboxylic acid amide and2.83 (both s, together 3H, amide rotamers), 2.49-2.36 (m, 2H), 2.00-1.89(m, 8H), 1.89-1.73 (m, 2H), 1.55-1.47 (m, 2H). SC_3152cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromo-2-morpholino-SC_3103 1H NMR (600 MHz, DMSO) δ 8.24 (s, 1H), 461.31,3-diazaspiro[4.5]decan-3-yl)-2- pyridine-4-carbonitrile 7.67-7.30 (m,5H), 7.29 (s, 1H), 3.70-3.65 (m, 4H), morpholin-4-yl-isonicotinonitrile3.51-3.44 (m, 4H), 2.37-2.22 (m, 2H), 2.10-1.87 (m, 10H), 1.53-1.31 (m,2H). SC_3153 cis-4-(8-Dimethylamino-2-oxo-8-phenyl- SC_3272 SC_3016 1HNMR (600 MHz, DMSO) δ 7.79 (d, 2H), 393.21,3-diazaspiro[4.5]decan-3-yl)- 7.62 (d, 2H), 7.41-7.34 (m, 4H), 7.27(td, 1H), benzamide 7.13-7.09 (m, 1H), 3.62 (s, 2H), 2.46-2.35 (m, 2H),1.97 (s, 6H), 1.93-1.76 (m, 4H), 1.51-1.45 (m, 2H). SC_3154cis-8-Dimethyamino-3-(2-fluoro-4- INT-976 1-bromo-2-fluoro-4- SC_3103 1HNMR (600 MHz, DMSO) δ 789-7.83 (m, 446.2methylsulfonyl-phenyl)-8-phenyl-1,3- methylsulfonyl-benzene 1H), 7.76(dd, 1H), 7.70 (dd, 1H), 7.40-7.32 (m, diazaspiro[4.5]decan-2-one 5H)7.29-7.23 (m, 1H), 3.69 (s, 2H), 3.23 (s, 3H), 2.43-2.30 (m, 2H), 1.96(s, 6H), 1.94-1.88 (m, 2H), 1.53-1.47 (m, 2H). SC_3155cis-4-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 4-bromo-3-fluoro- SC_31031H NMR (600 MHz, DMSO) δ 7.85-7.79 (m, 393.21,3-diazaspiro[4.5]decan-3-yl)-3-fluoro- benzonitrile 2H), 7.73 (s, 1H),7.62 (dd, 1H), 7.40-7.31 (m, benzonitrile 4H), 7.26 (tt, 1H), 3.69 (s,2H), 2.40-2.31 (m, 2H), 1.95 (s, 6H), 1.94-1.87 (m, 2H), 1.87-1.75 (m,2H), 1.52-1.46 (m, 2H). SC_3156 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-INT-976 4-bromo-3,5-difluoro- SC_3103 1H NMR (600 MHz, DMSO) δ 7.85 (d,2H), 411.2 1,3-diazaspiro[4.5]decan-3-yl)-3,5- benonitrile 7.61 (s, 1H),7.39-7.31 (m, 4H), 7.25 (tt, 1H), 3.53 (s, difluoro-benzonitrile 2H),2.42-2.33 (m, 2H), 1.98-1.89 (m, 8H), 1.82-1.78 (m, 2H), 1.54-1.47 (m,2H). SC_3157 cis-8-Dimethylamino-3-(2-methoxy- INT-989 methanol insteadof n- SC_3120 1H NMR (600 MHz, DMSO) δ 8.76 (s, 2H), 382.2pyrimidin-5-yl)-8-phenyl-1,3- butanol as a solvent 7.41-7.33 (m, 5H),7.27 (ddt, 1H), 3.86 (s, 3H), 3.60 (s, diazaspiro[4.5]decan-2-one 2H),2.47-2.30 (m, 2H), 2.01-1.74 (m, 10H), 1.52-1.45 (m, 2H). SC_3158cis-3-[2-(Benzylamino)-pyrimidin-5-yl]- INT-989 benzylamine SC_3120 1HNMR (600 MHz, DMSO) δ 8.43 (s, 2H), 457.3 8-dimethylamino-8-phenyl-1,3-7.50-7.45 (m, 1H), 7.46-7.33 (m, 5H), 7.31-7.23 (m,diazaspiro[4.5]decan-2-one 4H), 7.19 (tq, 1H), 4.46 (d, 2H), 4.02 (s,1H), 3.50 (s, 2H), 2.41-2.31 (m, 2H), 1.97 (s, 6H), 1.88 (s, 2H),1.49-1.41 (m, 2H). SC_3159 cis-8-Dimethylamino-3-[2-(4- INT-989(4-fluorophenyl)boronic SC_3129 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H),446.2 fluorophenyl)-pyrimidin-5-yl]-8-phenyl- acid 8.37-8.30 (m, 2H),7.83 (s, 1H), 7.44-7.35 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one7.34-7.25 (m, 3H), 3.69 (s, 2H), 2.47-2.30 (m, 2H), 2.08-1.80 (m, 10H),1.55-1.46 (m, 2H). SC_3160 trans-8-Benzyl-8-dimethylamino-3-(2- INT-9954-(5-bromopyrimidin-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.57 (s, 2H),451.3 morpholin-4-yl-pyrimidin-5-yl)-1,3- yl)morpholine 7.60 (s, 1H),7.27 (t, 2H), 7.22-7.15 (m, 3H), diazaspiro[4.5]decan-2-one 3.68-3.62(m, 4H), 3.64-3.57 (m, 4H), 3.49 (s, 2H), 2.66 (s, 2H), 2.22 (s, 6H),1.80-1.70 (m, 4H), 1.51-1.43 (m, 4H). SC_3161cis-8-Benzyl-8-dimethylamino-3-(2- INT-994 4-(5-bromopyrimidin-2-SC_3103 1H NMR (600 MHz, DMSO) δ 8.45 (s, 2H), 451.3morpholin-4-yl-pyrimidin-5-yl)-1,3- yl)morpholine 7.27 (t, 2H),7.22-7.15 (m, 3H), 7.11 (s, 1H), diazaspiro[4.5]decan-2-one 3.68-3.56(m, 8H), 2.64 (s, 2H), 2.26 (s, 6H), 1.87-1.77 (m, 4H), 1.42 (d, 2H),1.15 (dt, 2H). SC_3163 cis-4-(8-Dimethylamino-2-oxo-8-phenyl- SC_3156SC_3016 1H NMR (600 MHz, DMSO) δ 8.08 (s, 1H), 429.21,3-diazaspiro[4.5]decan-3-yl)-3,5- 7.65-7.58 (m, 2H), 7.48 (br s, 1H),7.39-7.31 (m, 4H), difluoro-benzamide 7.28-7.22 (m, 1H), 3.49 (s, 2H),2.40-2.32 (m, 2H), 1.96 (s, 6H), 1.95-1.90 (m, 2H), 1.87-1.77 (m, 2H),1.54-1.49 (m, 2H). SC_3164 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-SC_3155 SC_3016 1H NMR (600 MHz, DMSO) δ 7.95 (s, 1H), 411.21,3-diazaspiro[4.5]decan-3-yl)-3-fluoro- 7.72-7.64 (m, 2H), 7.61 (t,1H), 7.54-7.50 (m, 1H), benzamide 7.40-7.32 (m, 5H), 7.26 (tt, 1H), 3.62(s, 2H), 2.41-2.31 (m, 2H), 1.96 (s, 6H), 1.93-1.88 (m, 2H), 1.86-1.75(m, 2H), 1.53-1.45 (m, 2H). SC_3165 cis-8-Benzyl-8-dimethylamino-3-[2-INT-994 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 434.2(trifluoromethyl)-pyrimidin-5-yl]-1,3- (trifluoromethyl)pyrimidine 7.77(s, 1H), 7.29 (t, 2H), 7.24-7.17 (m, 3H), 3.55 (s,diazaspiro[4.5]decan-2-one 2H), 2.66 (s, 2H), 2.26 (s, 6H), 1.86 (dt,4H), 1.44 (d, 2H), 1.25-1.17 (m, 2H). SC_3166trans-8-Benzyl-8-dimethylamino-3-[2- INT-995 5-bromo-2- SC_3103 1H NMR(600 MHz, DMSO) δ 9.16 (s, 2H), 434.2(trifluoromethyl)-pyrimidin-5-yl]-1,3- (trifluoromethyl)pyrimidine 8.28(s, 1H), 7.27 (t, 2H), 7.22-7.16 (m, 3H), 3.67 (s,diazaspiro[4.5]decan-2-one 2H), 2.66 (s, 2H), 2.24 (s, 6H), 1.84-1.72(m, 4H), 1.49 (q, 4H). SC_3167 cis-8-Dimethylamino-8-thiophen-2-yl-3-INT-997 5-bromo-2- SC 3103 1H NMR (600 MHz, DMSO) δ 9.19 (d, 2H), 426.1[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3- (trifluoromethyl)pyrimidine7.97 (s, 1H), 7.43 (t, 1H), 7.07 (dd, 1H), 6.97 (d, 1H),diazaspiro[4.5]decan-2-one 3.78 (s, 2H), 2.40-2.27 (m, 2H), 2.04 (s,6H), 1.96 (t, 2H), 1.90-1.79 (m, 2H), 1.60-1.52 (m, 2H). SC_3168trans-8-Dimethylamino-8-thiophen-2-yl- INT-998 5-bromo-2- SC_3103 1H NMR(600 MHz, DMSO) δ 9.20 (s, 2H), 426.13-[2-(trifluoromethyl)-pyrimidin-5-yl]- (trifluoromethyl)pyrimidine 8.00(s, 1H), 7.45 (dd, 1H), 7.09 (dd, 1H), 1,3-diazaspiro[4.5]decan-2-one7.02-6.97 (m, 1H), 3.81 (s, 2H), 2.12 (d, 4H), 2.03 (s, 6H), 1.85 (t,2H), 1.62-1.54 (m, 2H). SC_3170 cis-8-Dimethylamino-8-phenyl-3-(2-INT-989 piperidine SC_3120 1H NMR (DMSO-d6): δ 8.49 (s, 2H), 7.39-7.24(m, 435.3 piperidin-1-yl-pyrimidin-5-yl)-1,3- 6H), 3.65-3.63 (m, 4H),3.50 (s, 2H), 2.36-2.32 (m, diazaspiro[4.5]decan-2-one 2H), 1.95-1.86(m, 10H), 1.61-1.56 (m, 2H), 1.50-1.44 (m, 6H). SC_3171cis-8-Dimethylamino-8-phenyl-3-(2- INT-989 pyrrolidine SC_3120 1H NMR(CDCl3): δ 8.43 (s, 2H), 7.41-7.38 (m, 421.3pyrrolidin-1-yl-pyrimidin-5-yl)-1,3- 2H), 7.32-7.30 (m, 3H), 5.05 (br s,1H), 3.53 (t, diazaspiro[4.5]decan-2-one 4H), 3.45 (s, 2H), 2.30-2.06(m, 10H), 1.99-1.96 (m, 6H), 1.62-1.58 (m, 2H). SC_3172cis-8-Dimethylamino-8-phenyl-3-(2- INT-989 pyrimidin-5-ylboronic SC_31291H NMR (600 MHz, DMF) δ 9.56 (s, 2H), 9.27 (s, 430,2pyrimidin-5-yl-pyrimidin-5-yl)-1,3- acid 1H), 9.17 (s, 2H), 8.35 (s,1H), 7.89 (d, 2H), diazaspiro[4.5]decan-2-one 7.63 (dq, 3H), 3.73 (s,2H), 3.04 (d, 2H), 2.81 (s, 6H), 2.57 (td, 2H), 2.06 (d, 2H), 1.58 (td,2H). SC_3174 trans-8-Benzyl-8-dimethylamino-3-[4- INT-9955-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.57(s, 1H), 447.2methyl-6-(trifluormethyl)-pyridin-3-yl]- (trifluoromethyl)pyridine 7.80(s, 1H), 7.67 (s, 1H), 7.27 (t, 2H), 7.23-7.15 (m,1,3-diazaspiro[4.5]decan-2-one 3H), 3.58 (d, 2H), 2.67 (s, 2H), 2.31 (s,3H), 2.22 (d, 6H), 1.82-1.72 (m, 4H), 1.56 (dd, 2H), 1.48 (td, 2H).SC_3175 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- SC_3152 SC_3016 480.61,3-diazaspiro[4.5]decan-3-yl)-2- morpholin-4-yl-pyridine-4-carboxylicacid amide SC_3176 cis-8-Dimethylamino-3-[2-(3,5- INT-989(3,5-dimethylisoxazol-4- SC_3129 1H NMR (600 MHz, DMSO) δ 9.05 (s, 2H),447.2 dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]- yl)boronic acid 7.80 (s,1H), 7.43-7.34 (m, 4H), 7.28 (tt, 1H), 3.68 (s,8-phenyl-1,3-diazaspiro[4.5]decan-2-one 2H), 2.69 (s, 3H), 2.47 (s, 3H),2.43-2.35 (m, 2H), 2.01-1.79 (m, 10H), 1.50 (s, 2H). SC_3177cis-3-[2-(Benzothiazol-6-yl)-pyrimidin- INT-989 1,3-benzothiazol-6-SC_3129 1H NMR (600 MHz, DMSO) δ 9.46 (s, 1H), 485.25-yl]-8-dimethylamino-8-phenyl-1,3- ylboronic acid 9.12 (s, 2H), 9.07(s, 1H), 8.49 (d, 1H), 8.16 (d, 1H), diazaspiro[4.5]decan-2-one 7.84 (s,1H), 7.39 (d, 4H), 7.29 (d, 1H), 3.73 (s, 2H), 2.42 (d, 2H), 1.97 (d,10H), 1.54 (d, 2H). SC_3178 cis-8-Dimethylamino-3-[2-fluoro-4- INT-9761-bromo-2-fluoro-4- SC_3103 1H NMR (600 MHz, DMSO) δ 7.80 (t, 1H), 436.2(trifluoromethyl)-phenyl]-8-phenyl-1,3- (trifluoromethyl)benzene 7.65(dd, 1H), 7.53 (dd, 1H), 7.40-7.32 (m, 4H), diazaspiro[4.5]decan-2-one7.29-7.23 (m, 1H), 3.66 (s, 2H), 2.36 (s, 2H), 1.97-1.88 (m, 8H),1.85-1.75 (m, 2H), 1.53-1.46 (m, 2H). SC_3179cis-8-Dimethylamino-3-(6-morpholin-4- INT-976 4-(5-bromo-2- as SC_3097step 2 1H NMR (600 MHz, DMSO) δ 8.20 (d, 1H), 7.89 436.3yl-pyridin-3-yl)-8-phenyl-1,3- pyridyl)morpholine 7.89 (dd, 1H), 7.37(p, 5H), 7.27 (d, 1H), 6.79 (d, 1H), diazaspiro[4.5]decan-2-one3.71-3.66 (m, 4H), 3.53 (s, 2H), 2.43-2.32 (m, 2H), 1.96 (s, 7H),1.91-1.85 (m, 5H), 1.49-1.42 (m, 2H). SC_3180cis-8-Dimethylamino-8-phenyl-3-(2- INT-976 4-bromo-2- SC_3103 1H NMR(DMSO-d6): δ 7.89-7.87 (m, 2H), 433.2 phenyl-thiazol-4-yl)-1,3-phenylthiazole 7.55 (br s, 1H), 7.43-7.35 (m, 8H), 7.29-7.26 (m, 1H),diazaspiro[4.5]decan-2-one 3.82 (s, 2H), 2.45 (br m, 2H), 1.96-1.79 (m,10H), 1.53-1.50 (m, 2H). SC_3181 cis-8-Dimethylamino-8-phenyl-3-[2-INT-989 tetrahydro-2H-pyran-4- SC_3103 1H NMR (DMSO-d6): δ 8.42 (s, 2H),7.39-7.35 (m, 451.3 (tetrahydro-pyran-4-ylamino)-pyrimidin- amine 5H),7.27-7.24 (m, 1H), 6.83 (d, 1H), 3.84-3.79 (m,5-yl]-1,3-diazaspiro[4.5]decan-2-one 3H), 3.50 (s, 2H), 3.38-3.35 (m,2H), 2.36-2.32 (m, 2H), 1.94-1.77 (m, 12H), 1.50-1.40 (m, 4H). SC_3183cis-8-Dimethylamino-8-phenyl-3-(4- INT-976 2-bromo-4- SC_3103 1H NMR(DMSO-d6): δ 8.09 (br s, 1H), 7.87 (d, 433.2 phenyl-thiazol-2-yl)-1,3-phenylthiazole 2H), 7.51 (s, 1H), 7.37-7.24 (m, 8H), 3.87 (s, 2H),diazaspiro[4.5]decan-2-one 2.43 (m, 2H), 1.96-1.84 (m, 10H), 1.54 (m,2H). SC_3184 cis-8-Dimethylamino-8-phenyl-3-[2- INT-976 1H-pyrrolo[2,3-SC_3103 1H NMR (DMSO-d6): δ 9.07 (s, 2H), 8.35-8.33 (m, 468.2(1H-pyrrolo[2,3-b)pyridin-1-yl)- b]pyridine 1H), 8.10-8.04 (m, 2H), 7.83(br s, 1H), pyrimidin-5-yl]-1,3- 7.41-7.37 (m, 4H), 7.29-7.21 (m, 2H),6.72-6.71 (d, 1H), diazaspiro[4.5]decan-2-one 3.71 (s, 2H), 2.49 (m,2H), 1.97 (m, 10H), 1.52 (m, 2H). SC_3185cis-8-Dimethylamino-8-phenyl-3-[2- INT-989 (3,4,5- SC_3129 IH NMR (600MHz, DMSO) δ 9.11 (s, 2H), 481.2(3,4,5-trifluoro-phenyl)-pyrimidin-5-yl]- trifluorophenyl)boronic8.12-8.03 (m, 2H), 7.89 (s, 1H), 7.42-7.34 (m, 4H),1,3-diazaspiro[4.5]decan-2-one acid 7.28 (dq, 1H), 3.71 (s, 2H),2.48-2.35 (m, 2H), 1.99-1.79 (m, 10H), 1.58-1.47 (m, 2H). SC_3187cis-8-Dimethylamino-3-m-tolyl-8- INT-976 1-bromo-3- SC_3186 363.2phenyl-1,3-diazaspiro[4.5]decan-2-one methylbenzene SC_3188cis-8-Dimethylamino-8-phenyl-3-p-tolyl- INT-976 1-bromo-4- SC_3186 363.21,3-diazaspiro[4.5]decan-2-one methylbenzene SC_3189cis-8-Dimethylamino-8-phenyl-3-[4- INT-976 1-bromo-4- SC_3186 417.2(trifluoromethyl)-phenyl]-1,3- trifluoromethylbenzenediazaspiro[4.5]decan-2-one SC_3190 cis-8-Dimethylamino-8-phenyl-3-[3-INT-976 1-bromo-3- SC_3186 433.2 (trifluoromethyloxy)-phenyl]-1,3-(trifluoromethoxy)benzene diazaspiro[4.5]decan-2-one SC_3191cis-8-Dimethylamino-8-phenyl-3-[4- INT-976 1-bromo-4- SC_3186 433.2(trifluoromethyloxy)-phenyl]-1,3- (trifluoromethoxy)benzenediazaspiro[4.5]decan-2-one SC_3192cis-2-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 methyl 2-bromobenzoateSC_3186 407.2 1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl esterSC_3193 cis-3-(8-Dimethylamino-2-oxo-8-pherlyl- INT-976 methyl3-bromobenzoate SC_3186 407.2 1,3-diazaspiro[4.5]decan-3-yl)-benzoicacid methyl ester SC_3194 cis-4-(8-Dimethylamino-2-oxo-8-phenyl- INT-976methyl 4-bromobenzoate SC_3186 407.21,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester SC_3195cis-3-(1,3-Benzodioxol-5-yl)-8- INT-976 5- SC_3186 393.2dimethylamino-8-phenyl-1,3- bromobenzo[d][1,3]dioxolediazaspiro[4.5]decan-2-one SC_3196 cis-8-Dimethylamino-8-phenyl-3-INT-976 5-bromoquinoline SC_3186 400.2quinolin-5-yl-1,3-diazaspiro[4.5]decan- 2-one SC_3197cis-3-(2,3-Dihydro-1H-indol-6-yl)-8- INT-976 6-bromoindoline SC_3186390.2 dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3198cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 methyl 5-bromo-4- SC_3186422.2 1,3-diazaspiro[4.5]decan-3-yl)-4-methyl- methylpicolinatepyridine-2-carboxylic acid methyl ester SC_3199cis-8-Dimethylamino-3-(6-methoxy-4- INT-976 5-bromo-2-methoxy-4- SC_3186394.2 methyl-pyridin-3-yl)-8-phenyl-1,3- methylpyridinediazaspiro[4.5]decan-2-one SC_3200 cis-8-Dimethylamino-3-[2-methyl-5-INT-976 5-bromo-1-methyl-3- SC_3186 421.2(trifluoromethyl)-2H-pyrazol-3-yl]-8- (trifluoromethyl)-1H-phenyl-1,3-diazaspiro[4.5]decan-2-one pyrazole SC_3201cis-8-Dimethylamino-3-(3-methoxy- INT-976 2-bromo-3- SC_3186 380.2pyridin-2-yl)-8-phenyl-1,3- methoxypyridine diazaspiro[4.5]decan-2-oneSC_3202 cis-8-Dimethylamino-8-phenyl-3-[5- INT-976 2-bromo-5- SC_3186418.2 (trifluoromethyl)-pyridin-2-yl]-1,3- trifluoromethylpyridinediazaspiro[4.5]decan-2-one SC_3203cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 3-bromo-5- SC_3186 375.21,3-diazaspiro[4.5]decan-3-yl)- cyanopyridine nicotinonitrile SC_3204cis-8-Dimethylamino-3-(3-methyl- INT-976 2-bromo-3- SC_3186 364.2pyridin-2-yl)-8-phenyl-1,3- methylpyridine diazaspiro[4.5]decan-2-oneSC_3205 cis-8-Dimethylamino-3-(6-methyl- INT-976 5-bromo-2- SC_3186380.2 pyridin-3-yl)-8-phenyl-1,3- methoxypyridinediazaspiro[4.5]decan-2-one SC_3206 cis-8-Dimethylamino-8-phenyl-3-[3-INT-976 1-bromo-3- SC_3186 417.2 (trifluoromethyl)phenyl]-1,3-trifluoromethylbenzene diazaspiro[4.5]decan-2-one SC_3207cis-3-(1,3-Benzodioxol-4-yl)-8- INT-976 4- SC_3186 393.2dimethylamino-8-phenyl-1,3- bromobenzo[d][1,3]dioxolediazaspiro[4.5]decan-2-one SC_3209 cis-8-Dimethylamino-3-[2-(3,5-INT-976 3,5-dimethyl-1H- SC_3103 1H NMR (DMSO-d6): δ 9.00 (s, 2H), 7.81(br s, 446.2 dimethyl-1H-pyrazol-1-yl)-pyrimidin-5- pyrazole 1H),7.38-7.27 (m, 5H), 6.07 (s, 1H), 3.69 (s, 2H),yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2- 2.45 (m, 5H), 2.17 (s, 3H),1.96-1.91 (m, 10H), one 1.51 (br m, 2H). SC_3210cis-8-Dimethylamino-3-[2-(3-hydroxy- INT-989 rac-piperidin-3-ol SC_31821H NMR (DMSO-d6): 8.48 (s, 2H), 7.39-7.35 (m, 451.2piperidin-1-yl)-pyrimidin-5-yl]-8- 5H), 7.27-7.24 (m, 1H), 4.82 (d, 1H),4.39-4.36 (m, phenyl-1,3-diazaspiro[4.5]decan-2-one 1H), 4.24-4.21 (m,1H), 3.51 (s, 2H), 3.41-3.36 (m, 1H), 2.92-2.87 (m, 1H), 2.77-2.72 (m,1H), 2.42-2.32 (m, 2H), 2.00-1.66 (m, 12H), 1.46-1.39 (m, 2H), 1.34 (t,2H). SC_3211 cis-8-Dimethylamino-3-[2-(3-hydroxy- INT-989rac-piperidin-3-ol SC_3182 1H NMR (DMSO-d6): 8.48 (s, 2H), 7.35 (m, 5H),451.3 piperidin-1-yl)-pyrimidin-5-yl]-8- 7.25 (m, 1H), 4.82 (d, 1H),4.39-4.37 (m, 1H), phenyl-1,3-diazaspiro[4.5]decan-2-one 4.24-4.21 (m,1H), 3.51 (s, 2H), 3.40-3.39 (m, 1H), 2.90-2.87 (m, 1H), 2.77-2.72 (m,1H), 2.37 (m, 2H), 2.00-1.66 (m, 12H), 1.45 (m, 2H), 1.34 (t, 2H).SC_3212 cis-8-Dimethylamino-3-[2-[4-(2- INT-989 2-piperazin-1-ylethanolSC_3120 1H NMR (600 MHz, DMSO) δ 8.53 (s, 2H), 480.3hydroxy-ethyl)-piperazin-1-yl]- 7.37 (p, 5H), 7.27 (d, 1H), 3.62 (t,4H), 3.53 (q, 4H), pyrimidin-5-yl]-8-phenyl-1,3- 2.49-2.27 (m, 7H), 1.96(s, 6H), 1.94-1.73 (m, diazaspiro[4.5]decan-2-one 4H), 1.51-1.40 (m,2H). SC_3213 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8- SC_3146 INT-991 1HNMR (600 MHz, DMSO) δ 8.53 (s, 2H), 494.3phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 7.57 (s, 1H), 7.42 (d, 4H), 7.33(d, 1H), 3.68 (t, 4H), pyrimidin-2-yl]-piperazin-1-yl]-acetic 3.19 (s,2H), 2.62 (t, 4H), 2.37 (d, 2H), acid 2.20-1.96 (m, 8H), 1.88 (t, 2H),1.43 (t, 2H). SC_3214 cis-8-Dimethylamino-3-[2-(1-methyl- INT-9891-methyl-4-(4,4,5,5- SC_3208 1H NMR (600 MHz, DMSO + 2vol % TFA) δ 484.31H-pyrrolo[2,3-b]pyridin-4-yl)- tetramethyl-1,3,2- 9.85 (s, 1H), 9.13(s, 2H), 8.41 (d, 2H), 7.99 (s, 1H), pyrimidin-5-yl]-8-phenyl-1,3-dioxaborolan-2-yl)-2,3- 7.72 (s, 2H), 7.66-7.46 (m, 4H), 7.30 (s, 1H),diazaspiro[4.5]decan-2-one dihydropyrrolo[2,3- 3.88 (s, 2H), 3.60 (s,6H), 2.77-2.71 (m, 2H), b]pyridine 2.30-2.26 (m, 2H), 1.94-1.89 (m, 2H),1.75 (s, 3H), 1.41-1.35 (m, 2H). SC_3215cis-8-Benzyl-8-dimethylamino-3-[4- INT-994 5-bromo-4-methyl-2- SC_31031H NMR (600 MHz, DMSO) δ 8.52 (s, 1H), 447.2methyl-6-(trifluoromethyl)-pyridin-3-yl]- (trifluoromethyl)pyridine 7.76(s, 1H), 7.23 (dd, 2H), 7.19-7.11 (m, 4H), 2.62 (s,1,3-diazaspiro[4.5]decan-2-one 2H), 2.27 (s, 6H), 2.25 (s, 3H), 1.86(td, 2H), 1.80 (dt, 2H), 1.57-1.49 (m, 2H), 1.09 (td, 2H). SC_3216trans-8-Dimethylamino-3-[4-methyl-6- INT-998 5-bromo-4-methyl-2- SC_31031H NMR (600 MHz, DMSO) δ 8.61 (s, 1H), 439.2(trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 7.83 (s,1H), 7.53-7.49 (m, 1H), 7.45 (dd, 1H),thiophen-2-yl-1,3-diazaspiro[4.5]decan- 7.09 (dd, 1H), 6.99 (dd, 1H),3.70 (s, 2H), 2.35 (s, 3H), 2-one 2.19-2.05 (m, 4H), 2.02 (s, 6H),1.93-1.85 (m, 2H), 1.64 (dt, 2H). SC_3217cis-8-Dimethylamino-3-[4-methyl-6- INT-997 5-bromo-4-methyl-2- SC_31031H NMR (600 MHz, DMSO) δ 8.58 (s, 1H), 439.2(trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 7.80 (s,1H), 7.45 (s, 1H), 7.42 (dd, 1H), 7.05 (dd, 1H),thiophen-2-yl-1,3-diazaspiro[4.5]decan- 6.95 (dd, 1H), 3.67 (s, 2H),2.33 (s, 3H), 2-one 2.32-2.25 (m, 2H), 2.04 (s, 6H), 2.00-1.92 (m, 2H),1.89-1.76 (m, 2H), 1.62 (dt, 2H). SC_3218cis-8-Dimethylamino-3-[2-(1,1-dioxo- INT-976 4-[5-bromo-4- SC_3103 1HNMR (600 MHz, DMSO) δ 8.65 (s, 1H), 553.2[1,4]thiazinan-4-yl)-4-(trifluoromethyl)- (trifluoromethyl)pyrimidin-7.42 (s, 1H), 7.41-7.31 (m, 5H), 7.25 (tt, 1H), 4.23 (t,pyrimidin-5-yl]-8-phenyl-1,3- 2-yl]-1,4-thiazinane 4H), 3.22 (t, 4H),2.40-2.26 (m, 2H), diazaspiro[4.5]decan-2-one 1,1-dioxide (prepared as1.97-1.88 (m, 8H), 1.87-1.75 (m, 2H), 1.54-1.42 (m, 2H). SC_3097 step 1)SC_3219 cis-8-Dimethylamino-8-(1-methyl-1H- INT-1000 5-bromo-2- SC_31031H NMR (600 MHz, DMSO) δ 9.14 (s, 2H), 474.2 benzoimidazol-2-yl)-3-[2-(trifluoromethyl)pyrimidine 8.65 (s, 1H), 7.63 (d, 1H), 7.51 (d, 1H),7.25 (ddd, 1H), (trifluoromethyl)-pyrimidin-5-yl]-1,3- 7.19 (ddd, 1H),4.02 (s, 3H), 3.61 (s, 2H), 2.26 (d, diazaspiro[4.5]decan-2-one 2H),2.18 (s, 6H), 2.16-2.09 (m, 2H), 1.87 (s, 2H), 1.78 (d, 2H). SC_3220cis-8-Dimethylamino-8-(1-methyl-1H- INT-1000 5-bromo-4-methyl-2- SC_31031H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 487.3benzoimidazol-2-yl)-3-[4-methyl-6- (trifluoromethyl)pyridine 8.10 (s,1H), 7.80 (s, 1H), 7.60 (d, 1H), 7.50 (d, 1H),(trifluoromethyl)-pyridin-3-yl]-1,3- 7.23 (ddd, 1H), 7.17 (td, 1H), 4.02(s, 3H), 3.50 (s, diazaspiro[4.5]decan-2-one 2H), 2.34-2.25 (m, 5H),2.19-2.09 (m, 8H), 1.90-1.74 (m, 4H). SC_3222cis-3-[2-(Benzyl-methyl-amino)- INT-976 N-benzyl-5-bromo-N- SC_3103 1HNMR (DMSO-d6): δ 8.52 (s, 2H), 7.39-7.33 (m, 471.2pyrimidin-5-yl]-8-dimethylamino-8- methylpyrimidin-2- 5H), 7.30-7.17 (m,6H), 4.81 (s, 2H), 3.52 (s, 2H), phenyl-1,3-diazaspiro[4.5]decan-2-oneamine 3.03 (s, 3H), 2.45-2.32 (m, 2H), 1.95-1.86 (m, 10H), 1.47-1.43 (m,2H). SC_3223 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 ethyl 5-SC_3103 (step 1), 1H NMR (DMSO-d6): δ 9.04 (s, 2H), 8.24-8.23 (m, 585.31,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2- bromopyrimidine-2- INT-991 (step2), 1H), 7.42-7.39 (m, 2H), 7.32-7.31 (m, 3H), 5.70 (s,[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]- carboxylate (step 1), SC_3133(step 3) 1H), 3.70-3.60 (m, 16H), 3.54-3.52 (m, 2H),ethyl]-pyrimidine-2-carboxylic acid 2,5,8,11- 3.35 (s, 3H), 2.21-2.00(m, 12H), 1.66-1.64 (m, 2H). amide tetraoxatridecan-13- amine (step 3)SC_3225 cis-8-Dimethylamino-3-[2-[(2-hydroxy- INT-9892-(methylamino)ethanol SC_3182 1H NMR (DMSO-d6): δ 8.46 (s, 2H),7.39-7.33 (m, 425.2 ethyl)-methyl-amino]-pyrimidin-5-yl]-8- 5H),7.27-7.24 (m, 1H), 4.62 (t, 1H), 3.61-3.50 (m,phenyl-1,3-diazaspiro[4.5]decan-2-one 6H), 3.08 (s, 3H), 2.36-2.33 (m,2H), 1.95-1.86 (m, 10H), 1.47-1.45 (m, 2H). SC_3226cis-3-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromo-4-methyl-2SC_3103 (step 1), 487.3 1,3-diazaspiro[4.5]decan-3-yl)-(trifluoromethyl)pyridine SC_3016 (step 2) benzamide SC_3227cis-8-Dimethylamino-3-[3-fluoro-5- INT-976 2-bromo-3-fluoro-5- SC_3186417.1 (trifluoromethyl)-pyridin-2-yl]-8-phenyl-(trifluoromethyl)pyridine 1,3-diazaspiro[4.5]decan-2-one SC_3228cis-8-Dimethylamino-3-(5-methyl- INT-976 2-bromo-5- SC_3186 459.1pyrazin-2-yl)-8-phenyl-1,3- methylpyrazine diazaspiro[4.5]decan-2-oneSC_3229 cis-8-Dimethylamino-3-(5-fluoro- INT-976 4-bromo-5- SC_3186433.2 pyrimidin-4-yl)-8-phenyl-1,3- fluoropyrimidinediazaspiro[4.5]decan-2-one SC_3230 cis-8-Dimethylamino-3-(5-fluoro-INT-976 2-bromo-5- SC_3186 458.1 pyrimidin-2-yl)-8-phenyl-1,3-fluoropyrimidine diazaspiro[4.5]decan-2-one SC_3231cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromopyrazine SC_3186 471.1pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2- one SC_3232cis-3-([2,1,3]Benzoxadiazol-5-yl)-8- INT-976 5-bromobenzo[c][1,2,5]-SC_3186 444.1 dimethylamino-8-phenyl-1,3- oxadiazolediazaspiro[4.5]decan-2-one SC_3233 cis-2-[2-(8-Dimethylamino-2-oxo-8-SC_3169 ammonium chloride SC_3133 1H NMR (600 MHz, DMSO) δ 7.73 (s, 1H),423.2 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 7.40-7.32 (m, 4H), 7.31 (s,1H), 7.26 (dd, 1H), 7.18 (td, phenoxy]-acetamide 1H), 6.98-6.91 (m, 2H),4.50 (s, 2H), 3.52 (s, 2H), 2.42-2.29 (m, 2H), 2.01-1.71 (m, 10H),1.55-1.48 (m, 2H). SC_3234 cis-8-Dimethylamino-8-phenyl-3-(5- INT-9764-(5-bromothiophen-2- SC_3103 1H NMR (DMSO-d6) δ 8.45-8.43 (d, 2H), 7.87(br 433.2 pyridin-4-yl-thiophen-2-yl)-1,3- yl)pyridine s, 1H), 7.54-7.53(d, 1H), 7.49-7.48 (m, 2H), diazaspiro[4.5]decan-2-one 7.38-7.27 (m,5H), 6.35-6.34 (d, 2H), 3.64 (s, 2H), 2.42 (m, 2H), 1.96-1.90 (m, 10H),1.51-1.49 (m, 2H). SC_3236 cis-8-Dimethylamino-3-(2-morpholin-4-INT-1002 morpholine SC_3120 1H NMR (600 MHz, DMSO) δ 8.07 (d, 1H), 437.3yl-pyrimidin-4-yl)-8-phenyl-1,3- 7.93 (s, 1H), 7.37 (dt, 5H), 7.27 (t,1H), 3.65 (s, 2H), diazaspiro[4.5]decan-2-one 3.58 (s, 8H), 2.40-2.27(m, 2H), 1.94 (s, 6H), 1.92-1.80 (m, 4H), 1.43 (d, 2H). SC_3237cis-3-[2-(3,4-Difluoro-phenyl)- INT-989 (3,4- SC_3129 1H NMR (600 MHz,DMSO) δ 9.08 (s, 2H), 463.2 pyrimidin-5-yl]-8-dimethylamino-8-difluorophenyl)boronic 8.22-8.12 (m, 2H), 7.54 (dt, 1H), 7.41-7.37 (m,4H), phenyl-1,3-diazaspiro[4.5]decan-2-one acid 7.29 (s, 1H), 3.70 (s,2H), 2.06-1.75 (m, 12H), 1.50 (d, 2H). SC_3241cis-2-[4-[5-(8-Dimethylamino-2-oxo-8- SC_3213 ammonium chloride SC_31331H NMR (600 MHz, DMSO) δ 8.53 (s, 2H), 493.3phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 7.38 (d, 5H), 7.27 (s, 1H), 7.23(s, 1H), 7.11 (s, 1H), pyrimidin-2-yl]-piperazin-1-yl]- 3.67 (t, 4H),3.54-3.50 (m, 2H), 2.89 (s, 2H), acetamide 2.47 (t, 4H), 2.39-2.35 (m,2H), 1.96 (s, 7H), 1.93-1.82 (m, 3H), 1.48-1.44 (m, 2H). SC_3243cis-8-Dimethylamino-3-[6-(4-methyl- INT-976 1-(5-bromo-2-pyridyl)-4-SC_3242 (step 2) 1H NMR (600 MHz, DMSO) δ 8.16 (d, 1H), 449.3piperazin-1-yl)-pyridin-3-yl]-8-phenyl- methyl-piperazine 7.86 (dd, 1H),7.41-7.33 (m, 4H), 7.32 (s, 1H), 7.27 (t, 1,3-diazaspiro[4.5]decan-2-one1H), 6.78 (d, 1H), 3.51 (s, 2H), 2.55-2.45 (m, 4H), 2.42-2.27 (m, 6H),2.21 (s, 3H), 1.96 (s, 6H), 1.93-1.73 (m, 4H), 1.46 (t, 2H). SC_3244cis-8-Dimethylamino-3-[2-(1,1-dioxo- INT-976 4-(5-bromo-4-methyl-SC_3103 1H NMR (600 MHz, DMSO) δ 8.20 (s, 1H), 499.3[1,4]thiazinan-4-yl)-4-methyl-pyrimidin- pyrimidin-2-yl)-1,4- 7.36 (h,4H), 7.30-7.17 (m, 2H), 4.23-4.17 (m, 4H),5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan- thiazinane 1,1-dioxide 3.13 (t,4H), 2.44-2.28 (m, 2H), 2.24 (s, 3H), 2-one 1.97 (s, 6H), 1.91 (d, 4H),1.55-1.44 (m, 2H). SC_3245 cis-8-Dimethylamino-8-phenyl-3-[2- INT-9765-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 9.17 (s, 2H), 419.2(trifluoromethyl)-pyrimidin-5-yl]-1,3- (trifluoromethyl)- 8.03 (s, 1H),7.38 (s, 4H), 7.28 (tt, 1H), 3.73 (s, 2H), diazaspiro[4.5]decan-2-onepyrimidine 2.49-2.35 (m, 2H), 1.97 (s, 6H), 1.97-1.92 (m, 2H), 1.90-1.73(m, 2H), 1.55-1.49 (m, 2H). SC_3246 cis-2-[8-Dimethylamino-1-(3-methoxy-INT-979 2-chloropyrimidine-5- SC_3103 1H NMR (600 MHz, DMSO) δ 9.02 (s,2H), 449.3 propyl)-2-oxo-8-phenyl-1,3- carbonitrile 7.40-7.31 (m, 5H),3.86 (s, 2H), 3.26 (s, 3H), diazaspiro[4.5]decan-3-yl]-pyrimidine-5-3.29-3.19 (m, 2H), 2.73-2.67 (m, 2H), 2.16 (td, 2H), 2.00 (s,carbonitrile 7H), 1.83 (dt, 2H), 1.50-1.40 (m, 5H). SC_3247cis-8-Dimethylamino-3-[2-(4-methyl- INT-989 1-Methylpiperazin SC_3120 1HNMR (600 MHz, DMSO) δ 8.54 (s, 2H), 450.3piperazin-1-yl)-pyrimidin-5-yl]-8- 7.48-7.33 (m, 5H), 7.31-7.21 (m, 1H),3.63 (dd, 4H), phenyl-1,3-diazaspiro[4.5]decan-2-one 2.45-2.29 (m, 6H),2.20 (s, 3H), 1.96 (s, 6H), 1.94-1.78 (m, 4H), 1.51-1.42 (m, 2H).SC_3248 cis-8-Dimethylamino-1-[(1-hydroxy- SC_3245 [1-[tert- INT-988(step 1) 1H NMR (600 MHz, DMSO) δ 9.24 (s, 2H), 504.3cyclobutyl)-methyl]-8-phenyl-3-[2- butyl(dimethyl)silyl]- 7.38 (d, 4H),7.27 (p, 1H), 3.89 (s, 2H), 2.73-2.67 (m,(trifluoromethyl)-pyrimidin-5-yl]-1,3- oxycyclobutyl]methyl 4- 2H), 2.26(ddd, 2H), 2.19 (tt, 2H), 2.08 (s, 1H), diazaspiro[4.5]decan-2-onemethylbenzenesulfonate 2.00 (s, 6H), 1.92 (qd, 2H), 1.73-1.64 (m, 1H),1.60-1.50 (m, 3H), 1.50-1.45 (m, 2H). SC_3249cis-2-[1-(3-Methoxy-propyl)-8- SC_3246 SC_3099 1H NMR (600 MHz, DMSO) δ9.05 (s, 2H), 435.3 methylamino-2-oxo-8-phenyl-1,3- 7.49-7.44 (m, 2H),7.34 (t, 2H), 7.21 (t, 1H), 3.90 (s,diazaspiro[4.5]decan-3-yl]-pyrimidine-5- 2H), 3.26 (s, 3H), 2.23 (td,2H), 2.07 (s, 1H), carbonitrile 1.91 (d, 5H), 1.86-1.78 (m, 2H), 1.73(tt, 2H), 1.42 (d, 2H). SC_3250 cis-8-Dimethylamino-8-phenyl-3-[6-INT-976 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.88 (d, 1H), 419.3(trifluoromethyl)-pyridin-3-yl]-1,3- (trifluoromethyl)pyridine 8.24 (dd,1H), 7.86 (s, 1H), 7.78 (d, 1H), 7.41-7.34 (m,diazaspiro[4.5]decan-2-one 4H), 7.27 (t, 1H), 3.69 (s, 2H), 2.42 (s,2H), 1.97 (s, 6H), 1.96-1.74 (m, 4H), 1.53-1.47 (m, 2H). SC_3251cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromopyridine-2-SC_3103 1H NMR (600 MHz, DMSO) δ 8.92 (d, 1H), 376.21,3-diazaspiro[4.5]decan-3-yl)-pyridine- carbonitrile 8.15 (dd, 1H),7.95 (br s, 1H), 7.90 (d, 1H), 2-carbonitrile 7.41-7.34 (m, 4H), 7.27(t, 1H), 3.69 (s, 2H), 2.44-2.40 (m, 2H), 1.97 (s, 6H), 1.96-1.89 (m,3H), 1.90-1.70 (m, 1H), 1.53-1.46 (m, 2H). SC_3252cis-8-Dimethylamino-3-(2-morpholin-4- INT-989 morpholine SC_3120 1H NMR(600 MHz, DMSO) δ 8.57 (s, 2H), 437.3 yl-pyrimidin-5-yl)-8-phenyl-1,3-7.46-7.42 (m, 1H), 7.40-7.34 (m, 4H), 7.27 (td, 1H),diazaspiro[4.5]decan-2-one 3.64 (dd, 4H), 3.59 (dd, 4H), 3.54 (s, 2H),2.46-2.29 (m, 2H), 1.96 (s, 7H), 1.93-1.73 (m, 3H), 1.50-1.44 (m, 2H).SC_3253 cis-8-Dimethylamino-3-(2-methyl- INT-976 5-bromo-2-methyl-SC_3103 1H NMR (600 MHz, DMSO) δ 8.86 (s, 2H), 366.3pyrimidin-5-yl)-8-phenyl-1,3- pyrimidine 7.69 (s, 1H), 7.41-7.33 (m,5H), 7.31-7.19 (m, 1H), diazaspiro[4.5]decan-2-one 3.62 (s, 2H), 2.53(s, 3H), 2.48-2.31 (m, 2H), 1.97 (s, 6H), 1.95-1.77 (m, 4H), 1.52-1.46(m, 2H). SC_3254 cis-8-Dimethylamino-1-[(2- SC_3253 2-methoxybenzylSC_3105 1H NMR (DMSO-d6) δ 8.90 (s, 2H), 7.39-7.34 (m, 486.2methoxyphenyl)-methyl]-3-(2-methyl- bromide 3H), 7.28-7.22 (m, 4H),6.95-6.87 (m, 2H), 4.58 (s, pyrimidin-5-yl)-8-phenyl-1,3- 2H), 3.89 (s,3H), 3.63 (s, 2H), 2.68-2.64 (m, 5H), diazaspiro[4.5]decan-2-one2.35-2.28 (m, 2H), 2.01 (s, 6H), 1.49-1.43 (m, 4H). SC_3255cis-1-[(1-Hydro-cyclobutyl)-methyl]- SC_3248 SC_3099 1H NMR (600 MHz,DMSO) δ 9.26 (s, 2H), 490.3 8-methylamino-8-phenyl-3-[2- 7.51 (d, 2H),7.34 (t, 2H), 7.22 (t, 1H), 3.92 (s, 2H),(trifluoromethyl)-pyrimidin-5-yl]-1,3- 3.41 (s, 1H), 2.31 (td, 2H), 2.15(td, 2H), 2.07 (d, 1H), diazaspiro[4.5]decan-2-one 1.93 (d, 7H), 1.83(dt, 2H), 1.67 (t, 1H), 1.56 (q, 1H), 1.47 (d, 2H). SC_3256cis-8-Dimethylamino-1-[(1-hydroxy- SC_3253 [1-[tert- INT-988 (step 1) 1HNMR (600 MHz, DMSO) δ 8.92 (s, 2H), 450.3cyclobutyl)-methyl]-3-(2-methyl- butyl(dimethyl)silyl]- 7.37 (d, 4H),7.27 (td, 1H), 3.79 (s, 2H), 3.27 (s, 1H), pyrimidin-5-yl)-8-phenyl-1,3-oxycyclobutyl]methyl 4- 2.72-2.65 (m, 2H), 2.54 (s, 3H), 2.25-2.19 (m,diazaspiro[4.5]decan-2-one methylbenzenesulfonate 2H), 2.16 (tt, 2H),2.07 (s, 2H), 2.00 (s, 6H), 1.95-1.86 (m, 2H), 1.67 (qd, 1H), 1.55 (td,2H), 1.51-1.42 (m, 3H). SC_3257 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-SC_3260 SC_3099 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 422.38-methylamino-8-phenyl-3-pyrimidin-5- 8.81 (s, 1H), 7.53-7.48 (m, 2H),7.33 (t, 2H), yl-1,3-diazaspiro[4.5]decan-2-one 7.24-7.18 (m, 1H), 3.86(s, 2H), 2.29 (td, 2H), 2.14 (tt, 2H), 2.07 (s, 1H), 1.96-1.87 (m, 8H),1.82 (td, 2H), 1.71-1.62 (m, 1H), 1.54 (dp, 1H), 1.49-1.43 (m, 2H).SC_3258 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromo-4-methyl-SC_3103 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 390.21,3-diazaspiro[4.5]decan-3-yl)-4-methyl- pyridine-2-carbonitrile 7.92(s, 1H), 7.61-7.57 (m, 1H), 7.42-7.32 (m, 4H), pyridine-2-carbonitrile7.25 (tt, 1H), 3.63 (s, 2H), 2.38 (d, 2H), 2.28 (s, 3H), 2.00-1.90 (m,9H), 1.90-1.72 (m, 1H), 1.59-1.49 (m, 2H). SC_3259cis-8-Dimethylamino-3-(2-methyl- SC_3253 2-(bromomethyl)pyridine SC_31051H NMR (DMSO-d6): δ 8.94 (s, 2H), 8.52-8.51 (m, 457.2pyrimidin-5-yl)-8-phenyl-1-(pyridin-2- 1H), 7.77-7.74 (m, 1H), 7.45-7.42(d, 1H), yl-methyl)-1,3-diazaspiro[4.5]decan-2- 7.38-7.22 (m, 6H), 4.47(s, 2H), 3.84 (s, 2H), one 2.66-2.63 (m, 2H), 2.54 (s, 3H), 2.06-2.03(m, 2H), 1.92 (s, 6H), 1.57-1.42 (m, 4H). SC_3260 INT-9765-bromopyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.98 (s, 2H), 352.28.76 (s, 1H), 7.78 (s, 1H), 7.41-7.34 (m, 4H), 7.31-7.24 (m, 1H), 3.65(s, 2H), 2.49-2.34 (m, 2H), 1.97 (s, 6H), 1.95-1.76 (m, 4H), 1.50 (t,2H). SC_3261 cis-8-Dimethylamino-1-[(1-hydroxy- SC_3260 [1-[tert-INT-988 (step 1) 1H NMR (600 MHz, DMSO) δ 9.04 (s, 2H), 436.3cyclobutyl)-methyl]-8-phenyl-3- butyl(dimethyl)silyl]- 8.80 (s, 1H),7.37 (d, 4H), 7.27 (p, 1H), 3.83 (s, 2H),pyrimidin-5-yl-1,3-diazaspiro[4.5]decan- oxycyclobutyl]methyl 4- 3.28(s, 1H), 2.72-2.65 (m, 2H), 2.23 (td, 1H), 2-one methylbenzenesulfonate2.17 (tt, 1H), 2.07 (s, 2H), 2.00 (s, 6H), 1.91 (dt, 2H), 1.72-1.63 (m,1H), 1.60-1.45 (m, 5H). SC_3262 cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-SC_3255 SC_3099 1H NMR (600 MHz, DMSO) δ 9.29 (s, 2H), 476.2methyl]-8-phenyl-3-[2-(trifluoromethyl)- 7.68-7.63 (m, 2H), 7.33 (t,2H), 7.26-7.18 (m, 1H), pyrimidin-5-yl]-1,3- 3.97 (s, 2H), 3.45 (s, 2H),2.43 (td, 2H), 2.14 (tt, diazaspiro[4.5]decan-2-one 2H), 1.99 (td, 2H),1.96-1.90 (m, 2H), 1.71-1.54 (m, 4H), 1.52-1.47 (m, 2H). SC_3263cis-8-Dimethylamino-3-(3- INT-976 1-bromo-3-fluoro- SC_3103 1H NMR (600MHz, DMSO) δ 7.58-7.50 (m, 368.2 fluorophenyl)-8-phenyl-1,3- benzene2H), 7.41-7.33 (m, 4H), 7.33-7.23 (m, 3H), diazaspiro[4.5]decan-2-one6.77-6.71 (m, 1H), 3.58 (s, 2H), 2.48-2.31 (m, 2H), 1.97 (s, 6H),1.92-1.80 (m, 4H), 1.47 (t, 2H). SC_3264 cis-8-Dimethylamino-3-(3-INT-976 1-bromo-3- SC_3103 1H NMR (600 MHz, DMSO) δ 8.13 (t, 1H), 428.2methylsulfonyl-phenyl)-8-phenyl-1,3- methylsulfonylbenzene 7.88 (d, 1H),7.65 (s, 1H), 7.53 (t, 1H), 7.47 (dt, 1H), diazaspiro[4.5]decan-2-one7.41-7.35 (m, 4H), 7.28 (qd, 1H), 3.66 (s, 2H), 3.16 (s, 3H), 2.49-2.36(m, 2H), 1.97 (s, 6H), 1.96-1.74 (m, 4H), 1.53-1.47 (m, 2H). SC_3265cis-8-Dimethylamino-3-(4- INT-976 1-bromo-4- SC_3103 1H NMR (600 MHz,DMSO) δ 7.83-7.70 (m, 428.2 methylsulfonyl-phenyl)-8-phenyl-1,3-methylsulfonylbenzene 5H), 7.41-7.34 (m, 4H), 7.27 (tt, J = 7.1, 1.9 Hz,diazaspiro[4.5]decan-2-one 1H), 3.65 (s, 2H), 3.12 (s, 3H), 2.49-2.31(m, 2H), 1.97 (s, 6H), 1.95-1.75 (m, 4H), 1.49 (t, J = 8.6 Hz, 2H).SC_3266 cis-8-Dimethylamino-8-phenyl-3- INT-976 3-bromopyridazineSC_3103 1H NMR (600 MHz, DMSO) δ 8.82 (dd, J = 4.6, 352.2pyridazin-3-yl-1,3-diazaspiro[4.5]decan- 1.4 Hz, 1H), 8.45 (dd, J = 9.2,1.4 Hz, 1H), 7.95 (br 2-one s, 1H), 7.55 (dd, J = 9.2, 4.5 Hz, 1H),7.42-7.34 (m, 4H), 7.28 (t, J = 6.8 Hz, 1H), 3.83 (s, 2H), 2.47-2.29 (m,1H), 1.97 (s, 10H), 1.54-1.48 (m, 2H). SC_3267cis-3-Methoxy-4-(8-methylamino-2-oxo- INT-976 4-bromo-3-methoxy- SC_3103(for step 1HNMR (DMSO-d6, 400 MHz) δ (ppm) = 391.28-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- benzonitrile (step 1) 1),SC_3099 (for 7.50-7.50 (m, 2H), 7.42-7.31 (m, 5H), 7.18 (bs, 2H),benzonitrile step 2) 3.83 (s, 3H), 3.64 (s, 2H), 2.05-21.99 (m, 2H),1.85 (bs, 5H), 1.70 (bs, 2H), 1.53-1.50 (m, 2H). SC_3268cis-8-Dimethylamino-3-(2- INT-976 1-bromo-2-luorobenzene SC_3103 1H NMR(600 MHz, DMSO) δ 7.46 (td, J = 8.0, 368.2 fluorophenyl)-8-phenyl-1,3-1.6 Hz, 1H), 7.40-7.32 (m, 5H), 7.26 (td, J = 6.7,diazaspiro[4.5]decan-2-one 3.3 Hz, 1H), 7.24-7.12 (m, 3H), 3.53 (s, 2H),2.37-2.33 (m, 2H), 1.96 (s, 6H), 1.95-1.74 (m, 4H), 1.49 (t, J = 9.3 Hz,2H). SC_3269 cis-8-Dimethylamino-8-phenyl-3-(2- INT-9765-bromo-2-phenyl- SC_3103 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 428.3phenyl-pyrimidin-5-yl)-1,3- pyrimidine 8.34-8.28 (m, 2H), 7.82 (s, 1H),7.52-7.42 (m, 4H), diazaspiro[4.5]decan-2-one 7.39 (s, 1H), 7.38 (s,3H), 7.28 (t, J = 4.8 Hz, 1H), 3.70 (s, 2H), 2.43-2.39 (m, 2H),2.06-1.72 (m, 10H), 1.52 (d, J = 10.8 Hz, 2H). SC_3270cis-8-Methylamino-1-(oxetan-3-yl- SC_3245 oxetan-3-ylmethyl 4- SC_3099(for 1H NMR (DMSO-d6): δ 9.24 (s, 2H), 7.49 (d, 2H), 476.2methyl)-8-phenyl-3-[2-(trifluoromethyl)- methylbenzenesulfonate step1),SC_3105 7.34 (t, 2H), 7.21 (t, 1H), 4.66-4.62 (m, 2H),pyrimidin-5-yl]-1,3- (step 2) (for step 2) 4.44 (t, 2H), 3.87 (s, 2H),3.55 (d, 2H), 3.28-3.23 (m, diazaspiro[4.5]decan-2-one 1H), 2.36 (m,1H), 2.20-2.14 (m, 2H), 1.95-1.91 (m, 5H), 1.84-1.77 (m, 2H), 1.43-1.40(m, 2H). SC_3271 cis-1-(Cyclopropyl-methyl)-8- SC_3245 (bromomethyl)-SC_3099 (for 1H NMR (DMSO-d6): δ 9.26 (s, 2H), 7.50 (d, 2H), 460.1methylamino-8-phenyl-3-[2- cyclopropane step1), SC_3105 7.35 (t, 2H),7.22 (t, 1H), 3.89 (s, 2H), 3.13 (d, 2H),(trifluoromethyl)-pyrimidin-5-yl]-1,3- (for step 2) 2.29-2.23 (m, 3H),1.92-1.82 (m, 7H), 1.47-1.44 (m, diazaspiro[4.5]decan-2-one 2H),1.08-1.05 (m, 1H), 0.52-0.48 (m, 2H), 0.36-0.36-0.32 (m, 2H). SC_3272cis-4-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 4-bromobenzonitrileSC_3103 1H NMR (600 MHz, DMSO) δ 7.82-7.71 (m, 375.21,3-diazaspiro[4.5]decan-3-yl)- 3H), 7.72-7.67 (m, 2H), 7.41-7.33 (m,4H), benzonitrile 7.30-7.23 (m, 1H), 3.63 (s, 2H), 2.45-2.39 (m, 2H),1.97 (s, 6H), 1.95-1.72 (m, 4H), 1.51-1.44 (m, 2H). SC_3273cis-8-Dimethylamino-3-(4- INT-976 1-bromo-4-fluoro- SC_3103 368.2fluorophenyl)-8-phenyl-1,3- benzene diazaspiro[4.5]decan-2-one SC_3274cis-2-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 2-bromobenzonitrileSC_3103 1H NMR (600 MHz, DMSO) δ 7.77 (dd, J = 7.5, 375.21,3-diazaspiro[4.5]decan-3-yl)- 1.6 Hz, 1H), 7.66 (ddd, J = 8.3, 7.5,1.6 Hz, 1H), benzonitrile 7.60 (s, 1H), 7.48 (dd, J = 8.3, 1.1 Hz, 1H),7.39-7.34 (m, 4H), 7.32 (td, J = 7.5, 1.1 Hz, 1H), 7.26 (tt, J = 7.5,1.6 Hz, 1H), 3.68 (s, 2H), 2.46-2.30 (m, 2H), 2.01-1.75 (m, 10H),1.59-1.50 (m, 2H). SC_3276 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-SC_3256 SC_3099 1H NMR (600 MHz, DMSO) δ 8.94 (s, 2H), 436.38-methylamino-3-(2-methyl-pyrimidin- 7.53-7.47 (m, 2H), 7.39-7.30 (m,2H), 7.24-7.17 (m, 5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan- 1H), 3.83(s, 2H), 3.54-3.36 (m, 2H), 2.56 (s, 3H), 2-one 2.28 (td, 2H), 2.18-2.09(m, 2H), 1.97-1.86 (m, 7H), 1.81 (td, 2H), 1.71-1.61 (m, 1H), 1.59-1.47(m, 1H), 1.49-1.42 (m, 2H). SC_3277cis-8-Dimethylamino-3-[2-(morpholin-4- INT-976 4-[(5-bromopyrimidin-2-SC_3103 1H NMR (600 MHz, DMSO) δ 8.93 (s, 2H),yl-methyl)-pyrimidin-5-yl]-8-phenyl-1,3- yl)methyl]morpholine 7.87-7.65(m, 1H), 7.42-7.34 (m, 4H), 7.28 (dq, 1H), diazaspiro[4.5]decan-2-one3.66-3.62 (m, 2H), 3.61 (s, 2H), 3.54 (t, 4H), 2.43 (t, 4H), 1.98 (s,6H), 1.96-1.74 (m, 4H), 1.52-1.46 (m, 2H). SC_3278cis-8-Dimethylamino-3-[2-(methyl- INT-989 N-methyltetrahydro-2H- SC_31201H NMR (DMSO-d6): δ 8.50 (s, 2H), 7.39-7.35 (m, 465.2tetrahydro-pyran-4-yl-amino)-pyrimidin- pyran-4-amine 5H), 7.27-7.24 (m,1H), 4.74-4.67 (m, 1H), 5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-3.94-3.90 (m, 2H), 3.50 (s, 2H), 3.39 (t, 2H), 2.93 (s, 2-one 3H), 2.35(m, 2H), 1.99-1.71 (m, 12H), 1.50-1.44 (m, 4H). SC_3279cis-5-[8-Dimethylamino-1-[(1-hydroxy- INT-990 (1-(tert- SC_3105 (step1), 1H NMR (DMSO-d6): δ 9.12 (s, 2H), 8.63 (t, 1H), 669.4cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-butyldimethylsilyloxy)cyclobutyl)methyl SC_3133 (step 2) 7.36-7.33 (m,4H), 7.26-7.23 (m, 1H), 5.25 (s, 1H),diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2- 4- 3.85 (s, 2H), 3.52-3.34 (m,16H), 3.35 (m, 2H), (2-methoxy-ethoxy)-ethoxy]-ethoxy]-methylbenzenesulfonate 3.19 (s, 3H), 2.69-2.66 (m, 2H), 2.25-2.13 (m,4H), ethyl]-pyrimidine-2-carboxylic acid (step 1), 2,5,8,11- 1.97 (s,6H), 1.92-1.87 (m, 2H), 1.57-1.44 (m, 6H). amide tetraoxatridecan-13-amine (step 2) SC_3280 cis-1-(Cyclopropyl-methyl)-3-(2-fluoro- INT-9761-bromo-2-fluoro-4- SC_3103 (for step 1H NMR (DMSO-d6): δ 7.86 (t, 1H),7.81-7.77 (m, 486.2 4-methylsulfonyl-phenyl)-8- (methylsulfonyl)benzene1), SC_3105 (step 1H), 7.73-7.70 (m, 1H), 7.45 (d, 2H), 7.31 (t, 2H),methylamino-8-phenyl-1,3- (step 1), 2), SC_3099 (step 7.19 (t, 1H), 3.85(s, 2H), 3.24 (s, 3H), 3.09 (d, 2H), diazaspiro[4.5]decan-2-one(Bromomethyl)cyclopropane 3) 2.29-2.22 (m, 3H), 1.93-1.90 (m, 5H), (step2) 1.74-1.68 (m, 2H), 1.49-1.46 (m, 2H), 1.04 (m, 1H), 0.51-0.46 (m,2H), 0.34-0.30 (m, 2H). SC_3281 cis-2-[[5-(8-Dimethylamino-2-oxo-8-INT-989 2- SC_3120 1H NMR (DMSO-d6): δ 8.48 (s, 2H), 7.39-7.35 (m, 438.2phenyl-1,3-diazaspiro[4.5]decan-3-yl)- (methylamino)acetamide 5H),7.27-7.25 (m, 2H), 6.89 (s, 1H), 4.08 (s, 2H),pyrimidin-2-yl]-methyl-amino]- hydrochloride 3.51 (s, 2H), 3.07 (s, 3H),2.36-2.33 (m, 2H), acetamide 1.94-1.86 (m, 10H), 1.45 (m, 2H). SC_3282cis-2-[[5-(8-Dimethylamino-2-oxo-8- INT-976 tert-butyl (5- SC_3103 (forstep 1H NMR (DMSO-d6): δ 8.45 (s, 2H), 7.39-7.33 (m, 424.2phenyl-1,3-diazaspiro[4.5]decan-3-yl)- bromopyrimidin-2- 1), SC_3100step 5H), 7.27-7.22 (m, 2H), 6.92 (s, 1H), 6.86 (t, 1H),pyrimidin-2-yl]amino]-acetamide yl)(cyanomethyl)carbamate 3 (for step 2)3.74 (d, 2H), 3.51 (s, 2H), 2.46-2.28 (m, 2H), (step 1) 1.95-1.86 (m,10H), 1.45 (m, 2H). SC_3283 cis-1-(Cyclopropyl-methyl)-8- SC_3284SC_3099 1H NMR (DMSO-d6): δ 8.61 (s, 1H), 7.82 (s, 1H), 473.3methylamino-3-[4-methyl-6- 7.46-7.44 (m, 2H), 7.30 (t, 2H), 7.18 (t,1H), (trifluoromethyl)-pyridin-3-yl]-8-phenyl- 3.80 (s, 2H), 3.08 (d,2H), 2.33-2.25 (m, 6H), 1,3-diazaspiro[4.5]decan-2-one 1.92-1.89 (m,5H), 1.72 (t, 2H), 1.56-1.53 (m, 2H), 1.04 (m, 1H), 0.51-0.46 (m, 2H),0.33-0.30 (m, 2H). SC_3284 cis-1-(Cyclopropyl-methyl)-8- INT-9845-bromo-4-methyl-2- SC_3103 1H NMR (DMSO-d6): δ 8.59 (s, 1H), 7.82 (s,1H), 487.3 dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine7.35-7.34 (m, 4H), 7.27-7.23 (m, 1H), 3.75 (s, 2H),(trifluoromethyl)-pyridin-3-yl]-8-phenyl- 3.06 (d, 2H), 2.71-2.68 (m,2H), 2.33-2.24 (m, 5H), 1,3-diazaspiro[4.5]decan-2-one 2.00 (m, 6H),1.59-1.56 (m, 2H), 1.46 (t, 2H), 1.02-0.99 (m, 1H), 0.53-0.48 (m, 2H),0.33-0.30 (m, 2H). SC_3285 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3239thiophene-2-carbonyl SC_3240 1H NMR (600 MHz, DMSO) δ 8.90 (s, 2H),477.2 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- chloride 8.08-8.04 (m, 1H),7.84 (dd, 1H), 7.71 (s, 1H), 7.38 (d,pyrimidin-2-yl]-thiophene-2-carboxylic 5H), 7.27 (td, 1H), 7.19 (dd,1H), 3.66 (s, 2H), acid amide 2.48-2.34 (m, 2H), 1.99-1.75 (m, 10H),1.51-1.48 (m, 2H). SC_3286 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3239benzoyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 10.84 (s, 1H), 471.3phenyl-1,3-diazaspiro[4.5]decan-3-y)- 8.91 (s, 2H), 7.98-7.93 (m, 2H),7.62-7.55 (m, 1H), pyrimidin-2-yl]-benzamide 7.50 (t, 2H), 7.39 (d, 4H),7.28 (dt, 1H), 3.67 (s, 2H), 2.48-2.32 (m, 2H), 2.05-1.76 (m, 10H),1.55-1.49 (m, 2H). SC_3287 cis-8-Dimethylamino-8-phenyl-3-(5- INT-9762-bromo-5- SC_3103 1H NMR (DMSO-d6): δ 7.80-7.70 (br s, 1H), 432.2phenyl-thiophen-2-yl)-1,3- phenylthiophene 7.52 (d, 2H), 7.38-7.28 (m,7H), 7.20-7.17 (m, 2H), diazaspiro[4.5]decan-2-one 6.27 (d, 1H), 3.61(s, 2H), 2.49 (m, 2H), 1.95-1.91 (m, 10H), 1.48 (m, 2H). SC_3288cis-1-(Cyclopropyl-methyl)-8- INT-984 1-bromo-2- SC_3103 1H NMR (CDCl3):δ 7.49 (d, 1H), 7.41-7.22 (m, 496.3 dimethylamino-3-[2-(methylsulfonyl-(methylsulfonylmethyl)benzene 8H), 4.45 (s, 2H), 3.64 (s, 2H), 3.15 (d,2H), methyl)-phenyl]-8-phenyl-1,3- 2.79 (s, 3H), 2.71-2.67 (m, 2H), 2.37(t, 2H), 2.06 (s, diazaspiro[4.5]decan-2-one 6H), 1.67-1.64 (m, 2H),1.55-1.44 (m, 2H), 1.10-1.06 (m, 1H), 0.57-0.52 (m, 2H), 0.39-0.35 (m,2H). SC_3289 cis-1-(Cyclopropyl-methyl)-8- SC_3288 SC_3099 1H NMR(DMSO-d6): δ 7.49-7.37 (m, 5H), 482.3 methylamino-3-[2-(methylsulfonyl-7.32-7.30 (m, 3H), 7.19-7.15 (m, 1H), 4.49 (s, 2H),methyl)-phenyl]-8-phenyl-1,3- 3.71 (s, 2H), 3.05 (d, 2H), 2.87 (s, 3H),2.26-2.20 (m, diazaspiro[4.5]decan-2-one 3H), 1.91-1.87 (m, 5H),1.71-1.56 (m, 4H), 1.03-1.01 (m, 1H), 0.49-0.45 (m, 2H), 0.31-0.28 (m,2H). SC_3290 cis-8-Dimethylamino-8-(3- INT-1024 1-bromo-2- SC_3103 1HNMR (600 MHz, DMSO) δ 7.46 (dd, 1H), 460.3fluorophenyl)-3-[2-(methylsulfonyl- (methylsulfonylmethyl)benzene 7.39(td, 2H), 7.33 (dd, 1H), 7.31-7.21 (m, 1H), methyl)-phenyl]-1,3- 7.18(d, 1H), 7.15 (dd, 1H), 7.08 (td, 1H), 4.50 (s, 2H),diazaspiro[4.5]decan-2-one 3.56 (s, 2H), 2.88 (s, 3H), 2.42-2.24 (m,2H), 1.99-1.89 (m, 8H), 1.88-1.75 (m, 2H), 1.60-1.48 (m, 2H). SC_3291cis-8-Dimethylamino-8-(4- INT-1025 1-bromo-2- SC_3103 1H NMR (600 MHz,DMSO) δ 7.46 (dd, 1H), 460.3 fluorophenyl)-3-[2-(methylsulfonyl-(methylsulfonylmethyl)benzene 7.43-7.34 (m, 3H), 7.33 (dd, 1H), 7.28(td, 2H), 7.16 (t, methyl)-phenyl]-1,3- 2H), 4.49 (s, 2H), 3.55 (s, 2H),2.88 (s, 3H), diazaspiro[4.5]decan-2-one 2.35-2.32 (m, 2H), 1.95 (s,6H), 1.94-1.88 (m, 2H), 1.88-1.65 (m, 2H), 1.59-1.47 (m, 2H). SC_3294cis-8-Dimethylamino-8-(3- INT-1024 4-(5-bromo-4-methyl- SC_3103 1H NMR(600 MHz, DMSO) δ 8.13 (s, 1H), 469.3fluorophenyl)-3-(4-methyl-2-morpholin- pyrimidin-2- 7.40 (td, 1H),7.22-7.11 (m, 4H), 7.08 (td, 1H), 4-yl-pyrimidin-5-yl)-1,3-yl)morpholine 3.69-3.60 (m, 8H), 2.34-2.31 (m, 2H), 2.20 (s, 3H),diazaspiro[4.5]decan-2-one 1.96 (s, 6H), 1.96-1.70 (m, 4H), 1.56-1.43(m, 2H). SC_3295 cis-3-[6-(4-Acetyl-piperazin-1-yl)-4- INT-9761-[4-(5-bromo-4-methyl- SC_3103 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ(ppm) = 491.3 methyl-pyridin-3-yl]-8-dimethylamino-pyridin-2-yl)-piperazin- 7.88 (s, 1H), 7.35-7.22 (m, 5H), 6.73 (s, 1H),8-phenyl-1,3-diazaspiro[4.5]decan-2-one 1-yl]-ethanone 6.64 (s, 1H),3.53-3.50 (m, 8H), 3.38 (s, 2H), 2.33-2.30 (m, 2H), 2.14 (s, 3H),2.03-1.88 (m, 13H), 1.56-1.51 (m, 2H). SC_3296cis-3-[2-(4-Acetyl-piperazin-1-yl)-4- INT-976 1-[4-(5-bromo-4-methyl-SC_3103 1H-NMR (DMSO-d6, 400 MHz at 100° C.), δ 492.3methyl-pyrimidin-5-yl]-8- pyrimidin-2-yl)- (ppm) = 8.11 (s, 1H),7.35-7.24 (m, 5H), 6.88 (s, dimethylamino-8-phenyl-1,3-piperazin-1-yl]-ethanone 1H), 3.73 (bs, 4H), 3.52 (bs, 4H), 3.38 (s,2H), diazaspiro[4.5]decan-2-one 2.33 (bs, 2H), 2.22 (s, 3H), 2.03-1.87(m, 13H), 1.56-1.53 (m, 2H). SC_3297 cis-8-Dimethylamino-3-(4-methyl-6-INT-976 5-bromo-2-chloro-4- SC_3103 (for step 1H-NMR (DMSO-d6, 400 MHzat 100° C.), δ 442.3 pyridin-4-yl-pyridin-3-yl)-8-phenyl-1,3-methyl-pyridine (step 1), 1), SC_3129 (for (ppm) = 8.65 (d, 2H, J = 5.92Hz), 8.50 (s, 1H), diazaspiro[4.5]decan-2-one 4-pyridinylboronic acidstep 2) 7.96 (d, 2H, J = 5.96 Hz), 7.91 (s, 1H), (step 2) 7.36-7.23 (m,5H), 7.07 (s, 1H), 3.57 (s, 2H), 2.38-2.33 (m, 5H), 2.04 (s, 6H),2.00-1.88 (m, 4H), 1.61-1.57 (m, 2H). SC_3298cis-3-[2-(4-Acetyl-piperazin-1-yl)-4- INT-976 1-[4-(5-bromo-4- SC_31031H-NMR (DMSO-d6, 400 MHz at 100° C.), δ 546.3(trifluoromethyl)-pyrimidin-5-yl]-8- trifluoromethyl- (ppm) = 8.52 (s,1H), 7.35-7.22 (m, 5H), 7.07 (s, dimethylamino-8-phenyl-1,3-pyrimidin-2-yl)- 1H), 3.79-3.78 (t, 4H, 5.08 Hz), 3.57 (t, 4H, 5.26 Hz),diazaspiro[4.5]decan-2-one piperazin-1-yl]-ethanone 3.39 (s, 2H),2.36-2.32 (m, 2H), 2.04-1.85 (m, 13H), 1.54-150 (m, 2H). SC_3299cis-8-Dimethylamino-3-[2-(3-oxo- INT-976 4-(5-bromo-4- SC_3103 1HNMR(DMSO-d6, 400 MHz), δ (ppm) = 8.55 (s, 518.2piperazin-1-yl)-4-(trifluoromethyl)- trifluoromethyl- 1H), 7.77 (bs,1H), 7.35-7.23 (m, 5H), 7.09 (s, 1H), pyrimidin-5-yl]-8-phenyl-1,3-pyrimidin-2-yl)- 4.20 (s, 2H), 3.92 (t, 2H, J = 5.04 Hz), 3.39 (s, 2H),diazaspiro[4.5]decan-2-one piperazin-2-one 3.33 (bs, 2H), 2.36-2.33 (m,2H), 2.03-1.85 (m, 10H), 1.54-1.39 (m, 2H). SC_3300cis-8-Dimethylamino-3-isoquinolin-4-yl- INT-976 4-bromo-isoquinolineSC_3103 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ (ppm) = 401.28-phenyl-1,3-diazaspiro[4.5]decan-2-one 9.16 (s, 1H), 8.41 (s, 1H), 8.13(d, 1H, J = 8.12 Hz), 7.91 (d, 1H, J = 8.64 Hz), 7.71 (t, 1H, J = 7.58Hz), 7.67 (t, 1H, J = 7.46 Hz), 7.36-7.23 (m, 5H), 7.14 (s, 1H), 3.67(s, 2H), 2.41-2.36 (m, 2H), 2.10-1.89 (m, 10H), 1.68-1.64 (m, 2H).SC_3301 cis-8-Dimethylamino-3-isoquinolin-5-yl- INT-9765-bromo-isoquinoline SC_3103 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ(ppm) = 401.2 8-phenyl-1,3-diazaspiro[4.5]decan-2-one 9.29 (s, 1H), 8.48(d, 1H, J = 5.92 Hz) 7.98-7.96 (m, 1H), 7.70-7.64 (m, 3H), 7.36-7.23 (m,5H), 7.13 (s, 1H), 3.65 (s, 2H), 2.41-2.36 (m, 2H), 2.10-1.90 (m, 10H),1.68-1.63 (m, 2H). SC_3302 cis-8-Dimethylamino-8-phenyl-3-(1H- INT-9764-bromo-1H-pyrrolo[2,3- SC_3103 1H NMR (600 MHz, DMSO) δ 11.42 (s, 1H),390.2 pyrrolo[2,3-b]pyridin-4-yl)-1,3- b]pyridine 7.99 (d, 1H), 7.66 (brs, 1H), 7.43-7.33 (m, 5H), diazaspiro[4.5]decan-2-one 7.27 (t, 1H), 7.22(t, 1H), 6.65-6.60 (m, 1H), 3.91 (s, 2H), 2.45-2.27 (m, 2H), 1.98-1.82(m, 10H), 1.56-1.49 (m, 2H). SC_3303 cis-8-Dimethylamino-8-phenyl-3-(2-INT-976 4-bromo-2-(pyridin-4- SC_3103 1H NMR (DMSO-d6): δ 8.62 (d, 2H),7.82 (d, 2H), 434.1 pyridin-4-yl-thiazol-4-yl)-1,3- yl)thiazole 7.61(broad s, 1H), 7.54 (s, 1H), 7.40-7.37 (m, 4H),diazaspiro[4.5]decan-2-one 7.29-7.27 (m, 1H), 3.84 (s, 2H), 2.49 (m,2H), 1.96-1.79 (m, 10H), 1.51 (m, 2H). SC_3304cis-8-[Methyl-(tetrahydro-furan-3-yl- INT-1026 4-(5-bromopyrimidin-2-step 2 of SC_3097 1H NMR (DMSO-d6): δ 8.56 (s, 2H), 7.65 (broad 507.3methyl)-amino]-3-(2-morpholin-4-yl- yl)morpholine (for synthesis), s,1H), 7.36-7.23 (m, 5H), 3.66-3.55 (m, 10H),pyrimidin-5-yl)-8-phenyl-1,3- SC_3292 and 3.49 (s, 2H), 3.38 (m, 1H),2.32-2.26 (m, 3H), diazaspiro[4.5]decan-2-one (enantiomer SC_3293 (for2.11-1.94 (m, 6H), 1.86-1.82 (m, 3H), 1.50-1.41 (m, 3H). 1) separationof enantiomers) SC_3305 cis-8-[Methyl-(tetrahydro-furan-3-yl- INT-10264-(5-bromopyrimidin-2- step 2 of SC_3097 1H NMR (DMSO-d6): δ 8.56 (s,2H), 7.66 (broad 507.2 methyl)-amino]-3-(2-morpholin-4-yl- yl)morpholine(for synthesis), s, 1H), 7.35-7.24 (m, 5H), 3.63-3.49 (m, 12H),pyrimidin-5-yl)-8-phenyl-1,3- SC_3292 and 3.31 (m, 1H), 2.27 (m, 3H),2.11-1.84 (m, 10H), diazaspiro[4.5]decan-2-one (enantiomer SC_3293 (for1.42 (m, 3H). 2) separation of enantiomers) SC_3306cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]- INT-9762-azetidin-1-yl-5-bromo- step 2 of SC_3242 1HNMR (DMSO-d6, 400 MHz at100° C.), δ (ppm) = 407.2 8-dimethylamino-8-phenyl-1,3- pyrimidine 8.48(s, 2H), 7.36-7.26 (m, 5H), 7.07 (s, 1H), diazaspiro[4.5]decan-2-one3.99 (t, 4H, J = 7.18 Hz), 3.50 (s, 2H), 2.35-2.26 (m, 4H), 2.03 (s,6H), 1.95-1.91 (m, 2H), 1.52-1.50 (m, 2H). SC_3307cis-3-[2-(3,3-Difluoro-azetidin-1-yl)- INT-976 5-bromo-2-(3,3-difluoro-step 2 of SC_3242 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ (ppm) = 443.2pyrimidin-5-yl]-8-dimethylamino-8- azetidin-1-yl)-pyrimidine 8.62 (s,2H), 7.37-7.25 (m, 5H), 7.20 (s, 1H),phenyl-1,3-diazaspiro[4.5]decan-2-one 4.38 (t, 4H, J = 12.40 Hz), 3.55(s, 2H), 2.36-233 (m, 2H), 2.03 (s, 6H) 1.97-1.89 (m, 4H), 1.53-1.51 (m,2H). SC_3308 cis-8-Dimethylamino-3-[6-morpholin-4- INT-976 4-(5-bromo-3-SC_3103 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ (ppm) = 504.3yl-5-(trifluoromethyl)-pyridin-3-yl]-8- trifluoromethyl-pyridin- 8.63(s, 1H), 8.38 (s, 1H), 7.37-7.25 (m, 6H),phenyl-1,3-diazaspiro[4.5]decan-2-one 2-yl)-morpholine 3.71 (bs, 4H),3.65 (s, 2H), 3.03 (bs, 4H), 2.37-2.32 (m, 2H), 2.03 (s, 6H), 1.98-1.88(m, 4H), 1.55-1.52 (m, 2H). SC_3309cis-8-Methylamino-3-[6-morpholin-4-yl- SC_3308 SC_3099 1HNMR (DMSO-d6,400 MHz at 100° C.), δ (ppm) = 490.45-(trifluoromethyl)-pyridin-3-yl]-8- 8.68 (s, 1H), 8.42 (s, 1H), 7.48(d, 2H, J = 8.12 Hz), phenyl-1,3-diazaspiro[4.5]decan-2-one 7.33 (t, 2H,J = 7.62 Hz), 7.20 (t, 1H, J = 7.38 Hz), 7.14 (s, 1H), 3.75-3.71 (m,6H), 3.03 (t, 4H, J = 8.88 Hz), 2.08-2.02 (m, 2H), 1.95-1.79 (m, 8H),1.58-1.55 (m, 2H). SC_3310 cis-8-Dimethylamino-8-phenyl-3-[5- INT-9762-bromo-5- SC_3103 1H NMR (600 MHz, DMSO) δ 8.32-8.26 (m, 435.2(trifluoromethyloxy)-pyridin-2-yl]-1,3- (trifluoromethoxy)- 2H),7.86-7.82 (m, 1H), 7.79 (dd, 1H), diazaspiro[4.5]decan-2-one pyridine7.41-7.33 (m, 4H), 7.27 (t, 1H), 3.71 (s, 2H), 2.46-2.33 (m, 2H), 1.96(s, 6H), 1.94-1.72 (m, 4H), 1.47 (t, 2H). SC_3311cis-8-Dimethylamino-3-(5- INT-976 2-bromo-5- SC_3103 1H NMR (600 MHz,DMSO) δ 8.66 (dd, 1H), 429.2 methylsulfonyl-pyridin-2-yl)-8-phenyl-methylsulfonylpyridine 8.39 (dd, 1H), 8.14 (dd, 1H), 8.06 (s, 1H),1,3-diazaspiro[4.5]decan-2-one 7.42-7.33 (m, 4H), 7.28 (t, 1H), 3.77 (s,2H), 3.21 (s, 3H), 2.46-2.32 (m, 2H), 2.03-1.68 (m, 10H), 1.52-1.46 (m,2H). SC_3312 cis-6-(8-Dimethylamino-2-oxo-8-phenyl- INT-9766-bromopyridine-3- SC_3103 1H NMR (600 MHz, DMSO) δ 8.66 (d, 1H), 376.21,3-diazaspiro[4.5]decan-3-yl)- carbonitrile 8.34 (d, 1H), 8.08 (dd,1H), 7.41-7.33 (m, 4H), 7.28 (t, nicotinonitrile 1H), 3.74 (s, 2H),2.46-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.73 (m, 4H), 1.51-1.44 (m, 2H),SC_3314 cis-8-Dimethylamino-3-[4-methyl-2-(3- INT-9764-(5-bromo-4-methyl- SC_3103 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ(ppm) = 464.2 oxo-piperazin-1-yl)-pyrimidin-5-yl]-8- pyrimidin-2-yl)-8.14 (s, 1H), 7.65 (bs, 1H), 7.34-7.23 (m, 5H),phenyl-1,3-diazaspiro[4.5]decan-2-one piperazin-2-one 6.89 (s, 1H), 4.16(s, 2H), 3.88 (bs, 2H), 3.39 (s, 2H), 3.29 (bs, 2H), 2.33 (bs, 2H), 2.24(s, 3H), 2.03-1.87 (m, 10H), 1.53 (bs, 2H). SC_3315cis-5-(8-Dimethylamino-2-oxo-8-phenyl- SC_3312 SC_3016 1H NMR (600 MHz,DMSO) δ 8.80 (d, 1H), 394.2 1,3-diazaspiro[4.5]decan-3-yl)-pyridine-8.10 (dd, 1H), 7.95-7.89 (m, 2H), 7.79 (s, 1H), 2-carboxylic acid amide7.42-7.35 (m, 5H), 7.28 (s, 1H), 3.67 (s, 2H), 2.48-2.28 (m, 2H), 1.95(d, 10H), 1.53-1.46 (m, 2H). SC_3316 cis-3-[4-(Azetidin-1-yl)-2-methyl-INT-976 4-azetidin-1-yl-5-bromo- step 2 of SC_3242 1HNMR (DMSO-d6, 400MHz at 100° C.), δ (ppm) = 421.2 pyrimidin-5-yl]-8-dimethylamino-8-2-methyl-pyrimidine 7.85 (s, 1H), 7.34-7.23 (m, 5H), 6.93 (s, 1H),phenyl-1,3-diazaspiro[4.5]decan-2-one 4.11 (t, 4H, J = 7.40 Hz), 3.33(s, 2H), 2.33-2.30 (m, 7H), 2.02 (s, 6H), 1.96-1.87 (m, 4H), 1.53-1.48(m, 2H). SC_3317 cis-2-(8-Dimethylamino-2-oxo-8-phenyl- INT-9762-bromobenzointrile SC_3103 (step 1), 1H NMR (600 MHz, DMSO) δ 7.50 (s,1H), 393.2 1,3-diazaspiro[4.5]decan-3-yl)- SC_3016 (step 2) 7.42 (dd,1H), 7.42-7.32 (m, 5H), 7.31 (d, 1H), 7.26 (t, benzamide 1H), 7.23-7.13(m, 3H), 3.53 (s, 2H), 2.41-2.27 (m, 2H), 1.96 (s, 6H), 1.90 (t, 2H),1.86-1.68 (m, 2H), 1.52-1.48 (m, 2H). SC_3318 cis-8-Dimethylamino-3-[2-INT-997 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 7.47 (dd, 1H), 448.2(methylsulfonyl-methyl)-pheny]-8- (methylsulfonylmethyl)- 7.43-7.36 (m,2H), 7.34 (dd, 1H), 7.29 (ddd, 1H),thiophen-2-yl-1,3-diazaspiro[4.5]decan- benzene 7.19 (s, 1H), 7.05 (ddd,1H), 6.94 (d, 1H), 4.50 (s, 2H), 2-one 3.61 (s, 2H), 2.89 (s, 3H),2.35-2.21 (m, 2H), 2.04 (s, 6H), 1.98-1.90 (m, 2H), 1.86-1.70 (m, 2H),1.66-1.59 (m, 2H). SC_3320 cis-8-Dimethylamino-3-(4-methyl-2- INT-9974-(5-bromo-4-methyl- SC_3319 1H NMR (600 MHz, DMSO) δ 8.15 (d, 1H),457.2 morpholin-4-yl-pyrimidin-5-yl)-8- pyrimidin-2- 7.41 (dt, 1H), 7.13(s, 1H), 7.05 (ddd, 1H), 6.94 (dd,thiophen-2-yl-1,3-diazaspiro[4.5]decan- yl)morpholine 1H), 3.71-3.60 (m,8H), 3.44 (s, 2H), 2-one 2.32-2.24 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H),1.98-1.88 (m, 2H), 1.87-1.75 (m, 2H), 1.62-1.54 (m, 2H). SC_3321cis-8-Dimethylamino-3-(6- INT-976 5-bromo-2- SC_3103 1H NMR (600 MHz,DMSO) δ 8.89 (d, J = 2.6 Hz, 429.2methylsulfonyl-pyridin-3-yl)-8-phenyl- methylsulfonylpyridine 1H), 8.28(dd, J = 8.9, 2.6 Hz, 1H), 7.93 (d, 1H), 1,3-diazaspiro[4.5]decan-2-one7.42-7.34 (m, 4H), 7.31-7.25 (m, 1H), 3.71 (s, 2H), 3.18 (s, 3H),2.48-2.33 (m, 2H), 2.04-1.76 (m, 10H), 1.54-1.48 (m, 2H). SC_3322cis-8-Dimethylamino-8-phenyl-3-(1H- INT-976 tert-butyl 5- SC_3103 (forstep 1H NMR (600 MHz, DMSO) δ 11.45 (s, 1H), 390.2pyrrolo[2,3-b]pyridin-5-yl)-1,3- bromopyrrolo[2,3- 1), SC_3173 (for 8.38(s, 1H), 8.00 (d, 1H), 7.85-7.81 (m, 1H), diazaspiro[4.5]decan-2-oneb]pyridine-1-carboxylate step 2) 7.70-7.66 (m, 2H), 7.57-7.53 (m, 3H),7.41 (t, 1H), (step 1) 6.35 (dd, 1H), 3.54 (s, 2H), 2.75-2.41 (m, 8H,overlapps with solvent residual peak), 2.30-2.26 (m, 2H), 1.89 (d, 2H),1.41-1.37 (m, 2H). SC_3323 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3239acetyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 10.36 (s, 1H), 409.2phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 8.82 (s, 2H), 8.40 (s, rotamer),7.67 (s, 1H), pyrimidin-2-yl]-acetamide (enantiomer 7.44-7.31 (m, 4H),7.27 (td, 1H), 3.62 (s, 2H), 2.46-2.30 (m, 1) 2H), 2.11 (s, 3H), 2.08(s, rotamer), 1.96 (s, 6H), 1.97 (s, rotamer), 1.95-1.75 (m, 4H),1.52-1.47 (m, 2H). SC_3324 cis-3-[2-(4-Methyl-piperazin-1-yl)- INT-10265-bromo-2-(4- step 2 of SC_3097 1H NMR (DMSO-d6): δ 8.52 (s, 2H), 7.64(broad 518.3 pyrimidin-5-yl]-8-[methyl-(tetrahydro- methylpiperazin-1-(for synthesis), s, 1H), 7.36-7.23 (m, 5H), 3.66-3.55 (m, 7H),furan-3-yl-methyl)-amino]-8-phenyl-1,3- yl)pyrimidine SC_3292 and 3.48(s, 2H), 3.37-3.36 (m, 1H), 2.33-2.13 (m, 11H),diazaspiro[4.5]decan-2-one (enantiomer SC_3293 (for 2.01-1.82 (m, 9H),1.50-1.41 (m, 3H). 2) separation of enantiomers) SC_3325cis-3-[2-(4-Methyl-piperazin-1-yl)- INT-1026 5-bromo-2-(4- step 2 ofSC_3097 1H NMR (DMSO-d6): δ 8.52 (s, 2H), 7.64 (broad 518.3pyrimidin-5-yl]-8-[methyl-(tetrahydro- methylpiperazin-1- (forsynthesis), s, 1H), 7.36-7.24 (m, 5H), 3.66-3.55 (m, 7H),furan-3-yl-methyl)-amino]-8-phenyl-1,3- yl)pyrimidine SC_3292 and 3.48(s, 2H), 3.36 (m, 1H), 2.34-2.13 (m, 10H), diazaspiro[4.5]decan-2-oneSC_3293 (for 2.01-1.83 (m, 10H), 1.50-1.41 (m, 3H). separation ofenantiomers) SC_3326 cis-8-Dimethylamino-3-(4,6-dimethyl-2- INT-9764-(5-bromo-4,6- SC_3103 — 465.3 morpholin-4-yl-pyrimidin-5-yl)-8-dimethyl-pyrimidin-2- phenyl-1,3-diazaspiro[4.5]decan-2-oneyl)morpholine SC_3327 cis-8-Dimethylamino-3-(2-morpholin-4- INT-1027morpholine SC_3120 1H NMR (600 MHz, DMSO) δ 8.58 (s, 2H), 443.2yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3- 7.43 (dd, 1H), 7.40-7.32 (m,1H), 7.07 (dd, 1H), diazaspiro[4.5]decan-2-one 6.96 (dd, 1H), 3.67-3.61(m, 4H), 3.62-3.57 (m, 6H), 2.31-2.27 (m 2H), 2.04 (s, 6H), 1.91 (t,2H), 1.86-1.82 (m, 2H), 1.56-1.50 (m, 2H). SC_3328cis-6-(8-Dimethylamino-2-oxo-8-phenyl- SC_3312 SC_3016 1H NMR (600 MHz,DMSO) δ 8.71 (d, J = 2.3 Hz, 394.21,3-diazaspiro[4.5]decan-3-yl)-pyridine- 1H), 8.24 (d, J = 8.9 Hz, 1H),8.12 (dd, J = 9.0, 2.4 Hz, 3-carboxylic acid amide 1H), 7.95 (s, 1H),7.86 (s, 1H), 7.36 (dq, J = 13.7, 6.6, 5.6 Hz, 5H), 7.27 (t, J = 7.2 Hz,1H), 3.74 (s, 2H), 2.41-2.37 (m, 2H), 1.96 (s, 6H), 1.94-1.87 (m, 2H),1.86-1.80 (m, 2H), 1.51-1.44 (m, 2H). SC_3329cis-8-Dimethylamino-3-[2-methyl-5- INT-997 5-bromo-1-methyl-3- SC_33191H NMR (600 MHz, DMSO) δ 7.66-7.63 (m, 428.2(trifluoromethyl)-2H-pyrazol-3-yl]-8- (trifluoromethyl)pyrazole 1H),7.42 (dd, 1H), 7.06 (dd, 1H), 6.95 (dd, 1H),thiophen-2-yl-1,3-diazaspiro[4.5]decan- 6.64 (s, 1H), 3.75 (s, 3H), 3.60(s, 2H), 2-one 2.30-2.26 (m, 2H), 2.04 (s, 6H), 1.98-1.90 (m, 2H),1.83-1.79 (m, 2H), 1.64-1.57 (m, 2H). SC_3330cis-8-Dimethylamino-3-[2-[(2-hydroxy- INT-1027 2-(methylamino)ethanolSC_3120 1H NMR (600 MHz, DMSO) δ 8.48 (s, 2H), 431.2ethyl)-methyl-amino]-pyrimidin-5-yl]-8- 7.43 (d, 1H), 7.30 (s, 1H), 7.07(dd, 1H), 6.96 (d, 1H), thiophen-2-yl-1,3-diazaspiro[4.5]decan- 3.61(dd, 2H), 3.58-3.51 (m, 4H), 3.09 (s, 3H), 2-one 2.34-2.22 (m, 2H), 2.04(s, 6H), 1.96-1.76 (m, 4H), 1.56-1.50 (m, 2H). SC_3331cis-8-Dimethylamino-3-[2-(2-oxo-1,3- INT-1027 4-(4,4,5,5-tetramethyl-SC_3208 1H NMR (600 MHz, DMSO) δ 10.46 (s, 1H), 489.2dihydro-indol-4-yl)-pyrimidin-5-yl]-8- 1,3,2-dioxaborolan-2- 9.12 (s,2H), 7.87 (d, 1H), 7.47-7.42 (m, 1H), 7.31 (t,thiophen-2-yl-1,3-diazaspiro[4.5]decan- yl)indolin-2-one 1H), 7.08 (dd,1H), 6.98 (dd, 1H), 6.92 (d, 1H), 2-one 3.83 (s, 2H), 3.77 (s, 2H),2.35-2.30 (m, 2H), 2.05 (s, 6H), 1.96 (t, 2H), 1.88 (s, 2H), 1.60-1.54(m, 2H). SC_3332 cis-8-Dimethylamino-3-[4-methyl-6-(3- INT-9764-(5-bromo-4-methyl- step 2 of SC_3097 1H-NMR (DMSO-d6, 400 MHz at 100°C.), δ (ppm) = 7.89 (s, 463.2 oxo-piperazin-1-yl)-pyridin-3-yl]-8-pyridin-2-yl)-piperazin- 1H), 7.62 (bs, 1H), 7.35-7.22 (m, 5H),phenyl-1,3-diazaspiro[4.5]decan-2-one 2-one 6.73 (s, 1H), 6.62 (s, 1H),3.96 (s, 2H), 3.68 (t, 2H, J = 5.2 Hz), 3.39 (s, 2H), 3.30 (bs, 2H),2.35-2.30 (m, 2H), 2.15 (s, 3H), 2.03-1.86 (m, 10H), 1.56-1.51 (m, 2H).SC_3333 cis-8-Dimethylamino-3-(4-methyl-6- INT-976 5-bromo-2-chloro-4-SC_3103 (for step 1H-NMR (DMSO-d6, 100 MHz at 100° C.), δ 442.3pyridin-2-yl-pyridin-3-yl)-8-phenyl-1,3- methyl-pyridine (step 1), 1),SC_3162 (for (ppm) = 8.64 (d, 1H, J = 4.0 Hz), 8.45 (s, 1H),diazaspiro[4.5]decan-2-one 2-tributylstannanyl- step 2) 8.31 (d, 1H, J =8.68 Hz), 8.22 (s, 1H), 7.88 (t, 1H, J = 7.04 Hz), pyridine (step 2)7.39-7.35 (m, 5H), 7.26-7.23 (m, 1H), 7.03 (s, 1H), 3.57 (s, 2H),2.39-2.33 (m, 5H), 2.04 (s, 6H), 2.01-1.88 (m, 4H), 1.61-1.57 (m, 2H).SC_3334 cis-8-Dimethylamino-3-(4- INT-976 3-bromo-4- SC_3103 (for step1HNMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm) = 8.77-8.72 (m, 429.3methylsulfonyl-pyridin-3-yl)-8-phenyl- methylsulfanyl-pyridine 1),SC_3008 (for 2H), 7.85-7.84 (m, 1H), 1,3-diazaspiro[4.5]decan-2-one(step 1) step 2) 7.35-7.23 (m, 6H), 3.60 (s, 2H), 3.31 (s, 3H), 2.36(bs, 2H), 2.03-1.82 (m, 10H), 1.60-1.58 (m, 2H). SC_3335cis-3-(Benzothiazol-7-yl)-8- INT-976 7-bromo-benzothiazole SC_3103 407.1dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3336cis-8-Dimethylamino-8-(4- INT-1025 4-(5-bromo-4-methyl- SC_3319 1H NMR(600 MHz, DMSO) δ 8.13 (s, 1H), 469.3fluorophenyl)-3-(4-methyl-2-morpholin- pyrimidin-2- 7.41-7.35 (m, 2H),7.22-7.13 (m, 3H), 3.69-3.60 (m, 4-yl-pyrimidin-5-yl)-1,3- yl)morpholine8H), 2.35-2.31 (m, 2H), 2.20 (s, 3H), 1.94 (s, 6H),diazaspiro[4.5]decan-2-one 1.93-1.74 (m, 4H), 1.53-1.43 (m, 2H). SC_3337cis-2-[8-Dimethylamino-3-[4-methyl-6- SC_3122 2-chloro-N,N-dimethyl-INT-988 (step 1) 1H NMR (600 MHz, DMSO) δ 8.59 (s, 1H), 518.3(trifluoromethyl)-pyridin-3-yl]-2-oxo-8- acetamide 7.82 (s, 1H),7.37-7.32 (m, 4H), 7.25 (ddd, 1H),phenyl-1,3-diazaspiro[4.5]decan-1-yl]- 4.00 (s, 2H), 3.80 (s, 2H), 3.07(s, 3H), 2.87 (s, 3H), N,N-dimethyl-acetamide 2.71-2.64 (m, 2H), 2.55(s, 3H), 2.34 (s, 3H), 2.03 (td, 2H), 1.98 (s, 6H), 1.67-1.58 (m, 2H),1.49-1.40 (m, 2H). SC_3338 cis-8-Dimethylamino-3-[2-(2-methyl-1- INT-9892-methyl-4-(4,4,5,5- SC_3208 1H NMR (600 MHz, DMSO) δ 9.57 (s, 1H),497.3 oxo-2,3-dihydro-isoindol-4-yl)- tetramethyl-1,3,2- 9.08 (s, 2H),8.52 (d, 1H), 8.43 (s, 1H), 7.77 (d, 1H), pyrimidin-5-yl]-8-phenyl-1,3-dioxaborolan-2- 7.72 (d, 2H), 7.63 (t, 1H), 7.59 (t, 2H), 7.55 (t, 1H),diazaspiro[4.5]decan-2-one yl)isoindolin-1-one 4.86 (s, 2H), 3.59 (s,2H), 3.13 (s, 3H), 2.72 (d, 2H), 2.61 (s, 6H), 2.25 (td, 2H), 1.91 (d,2H), 1.43-1.35 (m, 2H). SC_3339 cis-2-[[5-(8-Dimethylamino-2-oxo-8-INT-976 (5-bromo-2-methyl- step 2 of SC_3242 ¹HNMR at 100° C. (DMSO-d6,400 MHz), δ (ppm) = 7.93 (s, 438.4phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2- pyrimidin-4-ylamino)- (for step1), 1H), 7.36-7.22 (m, 5H), 7.12 (s, 1H),methyl-pyrimidin-4-yl]amino]-acetamide acetonitrile (step 1) SC_3016(for step 6.91 (bs, 2H), 6.58 (bs, 1H), 3.94 (d, 2H), 3.46 (s, 2H), 2)2.35-2.32 (m, 5H), 2.03-1.97 (m, 8H), 1.91-1.84 (m, 2H), 1.61-1.56 (m,2H). SC_3341 cis-8-Dimethylamino-3-[4- INT-976 3-bromo-4- step 2 ofSC_3097 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm) = 8.53 (s, 443.4(methylsulfonyl-methyl)-pyridin-3-yl]-8- methanesulfonylmethyl- 1H),8.43 (d, 1H, J = 4.88 Hz), 7.48 (d,phenyl-1,3-diazaspiro[4.5]decan-2-one pyridine 1H, J = 4.88 Hz),7.36-7.23 (m, 5H), 7.15 (s, 1H), 4.55 (s, 2H), 3.64 (s, 2H), 2.95 (s,3H), 2.38-2.33 (m, 2H), 2.04 (s, 6H), 1.99-1.83 (m, 4H), 1.62-1.57 (m,2H). SC_3342 cis-8-Dimethylamino-3-[6-(4-methyl-3- INT-9764-(5-bromo-2-pyridyl)-1- SC_3242 (step 2) 1H NMR (600 MHz, CDCl3) δ 8.09(d, 1H), 463.3 oxo-piperazin-1-yl)-pyridin-3-yl]-8-methyl-piperazin-2-one 8.00 (dd, 1H), 7.45-7.39 (m, 2H), 7.37-7.28 (m,3H), phenyl-1,3-diazaspiro[4.5]decan-2-one 6.61 (d, 1H), 5.71 (s, 1H),4.04 (s, 2H), 3.87-3.82 (m, 2H), 3.51 (s, 2H), 3.45 (t, 2H), 3.03 (s,3H), 2.32-2.02 (m, 10H), 2.02-1.94 (m, 2H), 1.64-1.53 (m, 2H). SC_3343cis-8-Dimethylamino-3-(2,4-dimethyl- INT-976 5-bromo-2,4-dimethyl-SC_3103 1H NMR (600 MHz, DMSO) δ 8.46 (s, 1H), 380.3pyrimidin-5-yl)-8-phenyl-1,3- pyrimidine 7.33 (m, 5H), 7.28-7.24 (m,1H), 3.51 (s, 2H), diazaspiro[4.5]decan-2-one 2.54 (s, 3H), 2.41-2.28(m, 5H), 2.03-1.77 (m, 10H), 1.56-1.49 (m, 2H). SC_3344cis-8-Dimethylamino-3-[2-(1-oxo-2,3- INT-989 4-(4,4,5,5-tetramethyl-SC_3208 1H NMR (600 MHz, DMSO) δ 9.06 (s, 2H) 483.3dihydro-isoindol-4-yl)-pyrimidin-5-yl]- 1,3,2-dioxaborolan-2- 8.67 (s,1H), 8.52 (d, 1H), 8.39 (s, 1H), 7.75 (dd, 3H),8-phenyl-1,3-diazaspiro[4.5]decan-2- yl)isoindolin-1-one 7.66-7.51 (m,4H), 4.75 (s, 2H), 3.58 (s, 2H), one; 2,2,2-trifluoro-acetic acid 3.18(s, 2H), 2.75 (d, 2H), 2.60 (s, 6H), 2.27 (t, 2H), 1.91 (d, 2H), 1.39(t, 2H). SC_3345 cis-8-Dimethylamino-3-[6-[(2-hydroxy- INT-9762-[[5-bromo-3- SC_3103 1H NMR (600 MHz, DMSO) δ 8.55-8.51 (m, 492.3ethyl)-methyl-amino]-5- (trifluoromethyl)-2- 1H), 8.35 (d, 1H), 7.62 (s,1H), 7.37 (td, 4H), (trifluoromethyl)-pyridin-3-yl]-8-phenyl-pyridyl]-methyl- (td, 1H), 3.63 (s, 2H), 3.50 (td, 2H), 3.20 (t, 2H),1,3-diazaspiro[4.5]decan-2-one amino]ethanol 2.78 (s, 3H), 2.43-2.36 (m,2H), 1.96 (s, 6H), 1.95-1.75 (m, 4H), 1.48 (t, 2H). SC_3346cis-8-Dimethylamino-8-phenyl-3-[2-[4- INT-976 3,3,3-trifluoroprop-1-SC_3313 1H NMR (600 MHz, DMSO) δ 9.56 (d, 1H), 487.3(trifluoromethyl)-1H-[1,2,3]triazol-1-yl]- yne, 2-azido-5-bromo- 9.16(s, 2H), 7.99 (s, 1H), 7.42-7.35 (m, 4H), pyrimidin-5-yl]-1,3-pyrimidine 7.31-7.25 (m, 1H), 3.75 (s, 2H), 2.49-2.34 (m, 2H),diazaspiro[4.5]decan-2-one 2.05-1.75 (m, 10H), 1.60-1.47 (m, 2H).SC_3347 cis-8-Dimethylamino-3-[2-(4-isopropyl- INT-9763-methylbut-1-yne, 2- SC_3313 1H NMR (600 MHz, DMSO) δ 9.10 (s, 2H),461.3 1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]- azido-5-bromo- 8.50 (d,1H), 7.91 (s, 1H), 7.42-7.35 (m, 5H), 7.28 (td,8-phenyl-1,3-diazaspiro[4.5]decan-2-one pyrimidine 1H), 3.73 (s, 2H),3.08 (hept, 1H), 2.44 (s, 2H), 2.01-1.76 (m, 10H), 1.59-1.48 (m, 2H),1.30 (d, 6H). SC_3348 cis-8-Dimethylamino-3-[6-(1,1-dioxo- INT-9761,4-thiazinane 1,1- SC_3242 1H NMR (600 MHz, DMSO) δ 8.23 (d, 1H), 484.2[1,4]thiazinan-4-yl)-pyridin-3-yl]-8- dioxide, 5-bromo-2- 7.93 (dd, 1H),7.41-7.33 (m, 5H), 7.27 (t, 1H), 6.98 (d,phenyl-1,3-diazaspiro[4.5]decan-2-one chloro-pyridine (step 1) 1H), 3.97(t, 4H), 3.53 (s, 2H), 3.04 (t, 4H), 2.43-2.28 (m, 2H), 1.96 (s, 6H),1.92-1.72 (m, 4H), 1.51-1.40 (m, 2H). SC_3349cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 5-bromo-2- SC_3242 1H NMR(600 MHz, DMSO-d6) δ 8.66 (d, J = 2.9 Hz, 461.31,3-diazaspiro[4.5]decan-3-yl)-2- chloropyridine-3- 1H), 8.25 (d, J =2.8 Hz, 1H), 7.60 (s, 1H), morpholin-4-yl-nicotinonitrile carbonitrile,morpholine 7.41-7.33 (m, 4H), 7.30-7.24 (m, 1H), 3.74-3.69 (m, 4H), 3.60(s, 2H), 2.48-2.29 (m, 2H), 1.96 (s, 6H), 1.94-1.68 (m, 4H), 1.52-1.41(m, 2H). SC_3350 cis-8-Dimethylamino-3-(1- INT-976 5-bromo-1- SC_3103 1HNMR (600 MHz, DMSO) δ 8.64 (d, 1H), 468.2 methylsulfonyl-1H-pyrrolo[2,3-methylsulfonyl- 8.28 (d, 1H), 7.65 (dd, 1H), 7.57 (s, 1H), 7.38 (dd,4H), b]pyridin-5-yl)-8-phenyl-1,3- pyrrolo[2,3-b]pyridine 7.28 (dt, 1H),6.72 (dd, 1H), 3.68 (s, 2H), 3.65 (s, diazaspiro[4.5]decan-2-one 3H),2.48-2.29 (m, 2H), 1.98 (s, 10H), 1.53-1.44 (m, 2H). SC_3351cis-8-Dimethylamino-3-(1H-indol-4-yl)- INT-976 4-bromo-1-(toluene-4-SC_3357 1H-NMR (DMSO-d6, 400 MHz at 100° C.), δ 389.38-phenyl-1,3-diazaspiro[4.5]decan-2-one sulfonyl)-1H-indole (step (ppm)= 10.77 (bs, 1H), 7.37 (bs, 4H), 1) 7.24-7.18 (m, 3H), 7.02-6.94 (m,2H), 6.81 (bs, 1H), 6.41 (s, 1H), 3.66 (s, 2H), 2.36-2.33 (m, 2H),2.05-1.96 (m, 10H), 1.60-156 (m, 2H). SC_3353cis-8-Dimethylamino-3-[2-fluoro-4- INT-976 1-bromo-2-fluoro-4- SC_31031H NMR (600 MHz, DMSO) δ 7.62 (t, 1H), 452.2(trifluoromethyloxy)-phenyl]-8-phenyl- (trifluoromethoxy)- 7.50-7.46 (m,1H), 7.40 (dd, 1H), 7.38-7.31 (m, 4H), 1,3-diazaspiro[4.5]decan-2-onebenzene 7.25 (t, 1H), 7.21 (d, 1H), 3.57 (s, 2H), 2.38 (d, 2H),1.97-1.88 (m, 8H), 1.84-1.79 (m, 2H), 1.53-1.46 (m, 2H). SC_3355cis-8-Dimethylamino-3-(1-methyl-1H- INT-976 4-bromo-1-methyl- SC_3103 1HNMR (600 MHz, DMSO) δ 8.04 (d, 1H), 404.3pyrrolo[2,3-b]pyridin-1-yl)-8-phenyl- pyrrolo[2,3-b]pyridine 7.70 (s,1H), 7.47 (d, 1H), 7.41-7.33 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one7.31-7.24 (m, 2H), 6.65 (d, 1H), 3.91 (s, 2H), 3.74 (s, 3H), 2.44-2.25(m, 2H), 2.08-1.74 (m, 10H), 1.52 (t, 2H). SC_3356cis-3-(1-Acetyl-1H-indol-4-yl)-8- SC_3351 acetyl chloride SC_3379 1H-NMR(DMSO-d6, 400 MHz at 100° C.), δ 431.2 dimethylamino-8-phenyl-1,3- (ppm)= 8.12 (d, 1H, J = 8.28 Hz), 7.68 (d, 1H, J = 3.64 Hz),diazaspiro[4.5]decan-2-one 7.36-7.22 (m, 6H), 7.16 (d, 1H, J = 7.80 Hz),7.01 (s, 1H), 6.69 (d, 1H, J = 3.8 Hz), 3.66 (s, 2H), 2.62 (s, 3H),2.38-2.33 (m, 2H), 2.05-1.92 (m, 10H), 1.61-1.56 (m, 2H). SC_3358cis-6-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 6-chloro-5-methyl-SC_3103 1H NMR (600 MHz, DMSO) δ 8.64 (s, 1H), 390.21,3-diazaspiro[4.5]decan-3-yl)-5-methyl- pyridine-3-carbonitrile 8.12(s, 1H), 7.76 (s, 1H), 7.39-7.34 (m, 4H), 7.27 (s, nicotinonitrile 1H),3.71 (s, 2H), 2.43-2.15 (m, 5H), 2.11-1.70 (m, 10H), 1.52 (s, 2H).SC_3359 cis-6-(8-Dimethylamino-2-oxo-8-phenyl- INT-9766-chloro-5-fluoro- SC_3103 1H NMR (600 MHz, DMSO) δ 8.64 (d, 1H), 394.21,3-diazaspiro[4.5]decan-3-yl)-5-fluoro- pyridine-3-carbonitrile 8.30(dd, 1H), 7.95 (s, 1H), 7.40-7.31 (m, 4H), nicotinonitrile 7.29-7.23 (m,1H), 3.72 (s, 2H), 2.36-2.33 (m, 2H), 1.96 (s, 6H), 1.94-1.79 (m, 4H),1.52 (t, 2H). SC_3361 cis-6-(8-Dimethylamino-2-oxo-8-phenyl- SC_3358SC_3016 1H NMR (600 MHz, DMSO) δ 8.64 (d, 1H), 408.21,3-diazaspiro[4.5]decan-3-yl)-5-methyl- 8.06-8.02 (m, 2H), 7.54 (s,1H), 7.44 (s, 1H), pyridine-3-carboxylic acid amide 7.38-7.30 (m, 4H),7.27-7.21 (m, 1H), 3.67 (s, 2H), 2.37-2.26 (m, 5H), 2.05-1.75 (m, 10H),1.51 (t, 2H). SC_3362 cis-6-(8-Dimethylamino-2-oxo-8-phenyl- SC_3359SC_3016 1H NMR (600 MHz, DMSO) δ 8.65-8.61 (m, 412.21,3-diazaspiro[4.5]decan-3-yl)-5-fluoro- 1H), 8.13 (s, 1H), 8.04 (dd,1H), 7.76 (s, 1H), pyridine-3-carboxylic acid amide 7.59 (s, 1H),7.39-7.30 (m, 4H), 7.28-7.21 (m, 1H), 3.70 (s, 2H), 2.41-2.23 (m, 2H),1.96-1.76 (m, 10H), 1.50 (t, 2H). SC_3363cis-8-Dimethylamino-3-[4-methyl-6- INT-1038 5-bromo-4-methyl-2- SC_33191H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 447.2(trifluoromethyl)-pyridin-3-yl]-8-m- (trifluoromethyl)pyridine 7.80 (s,1H), 7.52 (s, 1H), 7.24 (t, 1H), 7.17-7.11 (m,tolyl-1,3-diazaspiro[4.5]decan-2-one 2H), 7.06 (d, 1H), 3.60 (s, 2H),2.39-2.25 (m, 8H), 2.01-1.78 (m, 10H), 1.58-1.48 (m, 2H). SC_3364cis-3-(8-Dimethylamino-2-oxo-8-phenyl- INT-976 3-bromopyridine-4-SC_3242 1H NMR (600 MHz, DMSO) δ 8.79 (s, 1H), 376.21,3-diazaspiro[4.5]decan-3-yl)- carbonitrile 8.50 (d, 1H), 7.84-7.80 (m,1H), 7.37 (td, 4H), 7.26 (td, isonicotinonitrile 1H), 3.79 (s, 2H),2.43-2.36 (m, 2H), 1.97 (s, 7H), 1.96-1.91 (m, 2H), 1.88-1.81 (m, 2H),1.61-1.45 (m, 2H). SC_3365 cis-8-Dimethylamino-3-[3-fluoro-5-(2-INT-1045 4-(4,4,5,5-tetramethyl- SC_3354 1H NMR (600 MHz, DMSO) δ 10.51(s, 1H), 500.2 oxo-1,3-dihydro-indol-4-yl)-pyridin-2-1,3,2-dioxaborolan-2- 8.39 (d, 1H), 7.96 (dd, 1H), 7.41-7.32 (m, 4H),yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2- yl)indolin-2-one (step 2) 7.28(dt, 2H), 7.08 (d, 1H), 6.88 (d, 1H), 3.71 (s, 2H), one 3.67 (s, 2H),2.44-2.22 (m, 2H), 1.98-1.87 (m, 11H), 1.58-1.46 (m, 2H). SC_3366cis-8-Dimethylamino-3-[4-methyl-6- INT-1039 5-bromo-4-methyl-2- SC_33191H NMR (600 MHz, DMSO) δ 8.55 (s, 1H), 517.2(trifluoromethyl)-pyridin-3-yl]-8-[3- (trifluoromethyl)pyridine 7.79 (s,1H), 7.51 (t, 2H), 7.38 (dd, 1H), 7.26 (d, 2H),(trifluoromethyloxy)-phenyl]-1,3- 3.62 (s, 2H), 2.40-2.34 (m, 2H), 2.31(s, 3H), diazaspiro[4.5]decan-2-one 2.01-1.77 (m, 10H), 1.58-1.49 (m,2H). SC_3367 cis-8-Dimethylamino-3-[4-methyl-6- INT-10405-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) δ 8.55 (s, 1H), 501.2(trifluoromethyl)-pyridin-3-yl]-8-[3- (trifluoromethyl)pyridine 7.79 (s,1H), 7.69-7.56 (m, 5H), 7.52 (s, 1H), 3.61 (s,(trifluoromethyl)phenyl]-1,3- 2H), 2.44-2.36 (m, 2H), 2.31 (s, 3H),diazaspiro[4.5]decan-2-one 2.02-1.80 (m, 10H), 1.60-1.47 (m, 2H).SC_3368 cis-8-Dimethylamino-8-(3- INT-1041 5-bromo-4-methyl-2- SC_33191H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 463.2methoxyphenyl)-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H),7.51 (s, 1H), 7.31-7.25 (m, 1H), 6.92 (dt,(trifluoromethyl)-pyridin-3-yl]-1,3- 1H), 6.87-6.82 (m, 2H), 3.75 (s,3H), 3.61 (s, 2H), diazaspiro[4.5]decan-2-one 2.35-2.30 (m, 5H), 1.98(s, 7H), 1.96-1.90 (m, 2H), 1.88-1.80 (m, 2H), 1.60-1.49 (m, 2H).SC_3369 cis-8-(5-Chloro-thiophen-2-yl)-8- INT-1042 5-bromo-4-methyl-2-SC_3319 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 473.1dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine 7.79 (s, 1H),7.39 (s, 1H), 7.04-7.00 (m, 1H), 6.80 (d,(trifluoromethyl)-pyridin-3-yl]-1,3- 1H), 3.64 (s, 2H), 2.31 (s, 3H),2.22-2.15 (m, 2H), diazaspiro[4.5]decan-2-one 2.04 (s, 6H), 1.95-1.87(m, 2H), 1.83-1.77 (m, 2H), 1.63-1.57 (m, 2H). SC_3370cis-8-Dimethylamino-8-(3- INT-1024 5-bromo-4-methyl-2- SC_3319 1H NMR(600 MHz, DMSO) δ 8.56 (s, 1H), 451.2 fluorophenyl)-3-[4-methyl-6-(trifluoromethyl)pyridine 7.80 (s, 1H), 7.51 (s, 1H), 7.41 (td, 1H),7.21-7.12 (m, (trifluoromethyl)-pyridin-3-yl]-1,3- 2H), 7.12-7.06 (m,1H), 3.61 (s, 2H), diazaspiro[4.5]decan-2-one 2.38-2.30 (m, 5H), 1.97(s, 6H), 1.96-1.90 (m, 2H), 1.90-1.73 (m, 2H), 1.61-1.45 (m, 2H).SC_3371 cis-8-Dimethylamino-3-(2-methylamino- INT-989 methylamineSC_3239 1H NMR (600 MHz, DMSO + TFA) δ 8.69 (s, 2H), 381.2pyrimidin-5-yl)-8-phenyl-1,3- 8.29 (s, 1H), 7.68 (d, 2H), 7.52 (dt, 3H),2.90 (s, diazaspiro[4.5]decan-2-one 3H), 2.68 (d, 2H), 2.59 (s, 6H),2.24 (t, 2H), 1.86 (d, 2H), 1.39-1.31 (m, 2H) SC_3372cis-8-(5-Chloro-thiophen-2-yl)-8- INT-1042 4-(5-bromo-4-methyl- SC_32421H NMR (600 MHz, DMSO) δ 8.15 (d, 1H), 491.2dimethylamino-3-(4-methyl-2- pyrimidin-2- 7.15 (s, 1H), 7.05 (d, 1H),6.82 (d, 1H), 3.70-3.61 (m, morpholin-4-yl-pyrimidin-5-yl)-1,3-yl)morpholine 8H), 3.44 (s, 2H), 2.31-2.12 (m, 5H), 2.06 (s, 6H),diazaspiro[4.5]decan-2-one 1.93-1.85 (m, 2H), 1.82-1.69 (m, 2H),1.64-1.49 (m, 2H). SC_3373 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3371Cyclopropancarbonylchlorid SC_3240 1H NMR (600 MHz, DMSO) δ 8.97 (s,2H), 449.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 7.83-7.73 (m, 1H),7.41-7.34 (m, 4H), 7.30-7.24 (m, pyrimidin-2-yl]-N-methyl- 1H), 3.66 (s,2H), 3.27 (s, 3H), 2.47-2.29 (m, 2H), cyclopropanecarboxylic acid amide1.99-1.87 (m, 10H), 1.49 (t, 2H), 0.88-0.80 (m, 2H), 0.70 (dt, 2H).SC_3374 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_33712,5-dimethylpyrazole-3- SC_3240 1H NMR (600 MHz, DMSO) δ 8.83 (s, 2H),503.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- carbonyl chloride 7.77 (s,1H), 7.41-7.32 (m, 4H), 7.27 (td, 1H), 5.48 (s,pyrimidin-2-yl]-N,2,5-trimethyl-2H- 1H), 3.80 (s, 3H), 3.61 (s, 2H),3.40 (s, 3H), pyrazole-3-carboxylic acid amide 2.46-2.31 (m, 2H), 1.96(s, 3H), 1.96 (s, 6H), 1.94-1.74 (m, 5H), 1.52-1.42 (m, 2H). SC_3375cis-3-[4,6-Bis(trifluoromethyl)-pyridin- INT-976 5-bromo-2,4- SC_3103 1HNMR (600 MHz, DMSO) δ 8.98 (s, 1H), 487.23-yl]-8-dimethylamino-8-phenyl-1,3- bis(trifluoromethyl)pyridine 8.20(s, 1H), 7.79 (s, 1H), 7.40-7.32 (m, 4H), 7.26 (td,diazaspiro[4.5]decan-2-one 1H), 3.62 (s, 2H), 2.44-2.24 (m, 2H),1.98-1.91 (m, 8H), 1.86 (s, 2H), 1.53 (t, 2H). SC_3376cis-8-Dimethylamino-3-[2-[(2-hydroxy- INT-976 2-[(6-bromo-quinazolin-SC_3242 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm) = 475.1ethyl)-methyl-amino]-quinazolin-6-yl]-8- 2-yl)-methyl-amino]- 8.99 (s,1H), 8.28 (d, 1H, J = 9.24 Hz), 7.63 (s,phenyl-1,3-diazaspiro[4.5]decan-2-one ethanol 1H), 7.43-7.26 (m, 6H),7.13 (s, 1H), 4.31 (bs, 1H), 3.78-3.76 (m, 2H), 3.66 (bs, 4H), 3.24 (s,3H), 2.43-2.38 (m, 2H), 2.05-1.90 (m, 10H), 1.56-1.54 (m, 2H). SC_3377cis-8-Dimethylamino-3-(2-morpholin-4- INT-976 6-bromo-2-morpholin-4-SC_3242 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm) = 487.2yl-quinazolin-6-yl)-8-phenyl-1,3- yl-quinazoline 9.05 (s, 1H), 8.34 (d,1H), 7.68 (s, 1H), 7.48 (d, diazaspiro[4.5]decan-2-one 1H, J = 9.4 Hz),7.38-7.27 (m, 5H), 7.18 (s, 1H), 3.81-3.67 (m, 10H), 2.40-2.38 (m, 2H),2.05-1.90 (m, 10H), 1.57-1.54 (m, 2H). SC_3378cis-8-[Methyl-(oxetan-3-yl-methyl)- INT-1047 2-trifluoromethyl-5-SC_3103 1H NMR (DMSO-d6): δ 9.21-9.15 (s, 2H), 476.2amino]-8-phenyl-3-[2-(trifluoromethyl)- bromopyrimidine 8.19-8.18 (broads, 1H), 7.41-7.34 (m, 4H), pyrimidin-5-yl]-1,3- 7.27-7.25 (m, 1H),4.58-4.56 (m, 2H), 4.18 (s, 1H), 3.69 (s, diazaspiro[4.5]decan-2-one2H), 3.05-2.99 (m, 1H), 2.41-2.36 (m, 4H), 1.91 (m, 7H), 1.47 (s, 2H).SC_3380 cis-8-Dimethylamino-8-phenyl-3- INT-976 6-bromo-quinazolineSC_3103 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm) = 402.2quinazolin-6-yl-1,3- 9.35 (s, 1H), 9.10 (s, 1H), 8.65 (d, 1H, J = 9.04)diazaspiro[4.5]decan-2-one 7.91-7.89 (m, 2H), 7.39-7.27 (m, 5H), 3.75(s, 2H), 2.42-2.32 (m, 2H), 2.05 (s, 6H), 2.00-1.92 (m, 4H), 1.56 (bs,2H). SC_3381 cis-5-(8-Dimethylamino-2-oxo-8-phenyl- INT-9765-bromo-2-chloro- SC_3103 (for step 1H NMR (600 MHz, DMSO) δ 8.88 (s,1H), 507.3 1,3-diazaspiro[4.5]decan-3-yl)-2-(2-oxopyridine-4-carbonitrile 1), SC_3129 (for 8.24 (s, 1H), 7.85 (s, 1H),7.52-7.46 (m, 1H), 1,3-dihydro-indol-4-yl)-isonicotinonitrile (step 1),4-(4,4,5,5- step 2) 7.41-7.29 (m, 6H), 7.27 (td, 1H), 6.92 (d, 1H), 3.84(s, tetramethyl-1,3,2- 2H), 3.78 (s, 2H), 2.48-2.30 (m, 2H),dioxaborolan-2- 1.99-1.93 (m, 8H), 1.92-1.74 (m, 2H), 1.58-1.54 (m, 2H).yl)indolin-2-one (step 2) SC_3382 cis-N-[5-(8-Dimethylamino-2-oxo-8-SC_3371 tetrahydropyran-4- SC_3240 1H NMR (600 MHz, DMSO) δ 8.97 (s,2H), 493.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl)- carbonyl chloride 7.80(s, 1H), 7.42-7.34 (m, 4H), 7.31-7.25 (m, 1H),pyrimidin-2-yl]-N-methyl-tetrahydro- 3.79 (ddd, 2H), 3.67 (s, 2H), 3.25(s, 2H), 3.17 (td, pyran-4-carboxylic acid amide 2H), 3.04-2.96 (m, 1H),2.49-2.34 (m, 2H), 1.97 (s, 6H), 1.95-1.74 (m, 4H), 1.68-1.53 (m, 4H),1.54-1.48 (m, 2H). SC_3383 cis-N-[5-(8-Dimethylamino-2-oxo-8- SC_3371pivaloyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 8.98 (s, 2H), 465.3phenyl-1,3-diazaspiro[4.5]decan-3-yl)- 7.42-7.34 (m 4H), 7.30-7.26 (m,1H), 3.69 (s, 2H), pyrimidin-2-yl]-N,2,2-trimethyl- 3.14 (s, 3H),2.46-2.41 (m, 2H), 1.99-1.87 (m, propionamide 10H), 1.54-1.45 (m, 2H),0.97 (s, 9H). SC_3384 cis-8-Dimethylamino-3-[2-(1-methyl-2- INT-9891-methyl-4-(4,4,5,5- SC_3208 1H NMR (600 MHz, CDCl3) δ 9.05 (s, 2H),497.3 oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5- tetramethyl-1,3,2- 8.08(d, 1H), 7.47-7.39 (m, 3H), 7.38-7.31 (m, 3H),yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2- dioxoborolan-2- 6.91 (d, 1H),5.46 (s, 1H), 4.04 (s, 2H), 3.64 (s, one yl)indolin-2-one 2H), 3.27 (s,3H), 2.35-2.14 (m, 4H), 2.10 (s, 6H), 2.08-2.01 (m, 3H), 1.73-1.64 (m,2H), 1.28 (s, 0H). SC_3385 cis-8-Dimethylamino-3-(2-morpholin-4- INT-9766-bromo-1-(tert- SC_3242 (for step 1HNMR at 100° C. (DMSO-d6, 400 MHz),δ (ppm) = 475.2 yl-1H-benzoimidazol-5-yl)-8-phenyl-1,3- butylsilanyl-1), step 2 of 10.94 (bs, 1H), 7.50 (bs, 1H), 7.39-7.27 (m, 5H),diazaspiro[4.5]decan-2-one methoxymethyl)-2- SC_3352 (for step 7.06 (m,2 H), 6.84 (bs, 1H), 3.72 (t, 4H, 4.56 Hz), morpholin-4-yl-1H- 2) 3.55(s, 2H), 3.45 (t, 4H, 4.56 Hz), 2.372.24 (m, benzoimidazole (step 1)2H), 1.95-1.81 (m, 10H), 1.52-1.50 (m, 2H) SC_3386cis-8-Dimethylamino-8-(3-fluoro-5- INT-1043 5-bromo-4-methyl-2- SC_33191H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 465.2methyl-phenyl)-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H),7.51 (s, 1H), 6.99 (s, 1H), 6.96-6.89 (m,(trifluoromethyl)-pyridin-3-yl]-1,3- 2H), 3.61 (s, 2H), 2.34 (s, 3H),2.32 (s, 3H), 2.07 (s, diazaspiro[4.5]decan-2-one 1H), 1.97 (s, 6H),1.96-1.89 (m, 2H), 1.88-1.78 (m, 2H), 1.54 (d, 2H). SC_3387cis-8-Dimethylamino-3-[6-(2-oxo-1,3- INT-1048 4-(4,4,5,5-tetramethyl-SC_3129 1H NMR (600 MHz, DMSO) δ 8.83 (d, 1H), 482.3dihydro-indol-4-yl)-pyridin-3-yl]-8- 1,3,2-dioxaborolan-2- 8.11 (dd,1H), 7.77 (d, 1H), 7.64 (s, 1H), 7.43-7.34 (m,phenyl-1,3-diazaspiro[4.5]decan-2-one yl)indolin-2-one 5H), 7.31-7.24(m, 2H), 6.84 (d, 1H), 3.73 (s, 2H), 3.68 (s, 2H), 2.45-2.31 (m, 2H),1.99-1.79 (m, 10H), 1.51 (t, 2H). SC_3389 cis-3-[6-(Azetidin-1-yl)-5-INT-976 5-bromo-2-chloro-3- SC_3103 (for step 1H NMR 600 MHz, DMSO) δ8.40 (d, 1H), (trifluoromethyl)-pyridin-3-yl]-8-(trifluoromethyl)pyridine 1), SC_3120 (for 8.21 (d, 1H), 7.47 (s, 1H),7.41-7.33 (m, 4H), 453.2 dimethylamino-8-phenyl-1,3- (step 1), azetidine(step step 2, 160° C. 7.30-7.24 (m, 1H), 4.03 (t, 4H), 3.58 (s, 2H),diazaspiro[4.5]decan-2-one 2) 2.47-2.29 (m, 2H), 2.25 (p, 2H), 1.96 (s,6H), 1.89 (s, 4H), 1.47 (t, 2H). SC_3390cis-3-[1-(Cyclopropyl-methyl)-8- SC_3364 bromomethylcyclopropane INT-9521H NMR (600 MHz, DMSO) δ 8.82 (s, 1H), 430.3dimethylamino-2-oxo-8-phenyl-1,3- 8.51 (dd, 1H), 7.81 (d, 1H), 7.40-7.33(m, 4H), diazaspiro[4.5]decan-3-yl]- 7.29-7.23 (m, 1H), 3.93 (s, 2H),3.10 (d, 2H), isonicotinonitrile 2.76-2.70 (m, 2H), 2.29 (ddd, 2H), 2.02(s, 6H), 1.58 (d, 2H), 1.52-1.44 (m, 2H), 1.01 (ddt, 1H), 0.55-0.49 (m,2H), 0.37-0.31 (m, 2H). SC_3391 cis-3-[3,5-Bis(trifluoromethyl)-pyridin-INT-976 2-chloro-3,5- SC_3103 1H NMR (600 MHz, DMSO) δ 9.04 (d, 1H),487.2 2-yl]-8-dimethylamino-8-phenyl-1,3- bis(trifluoromethyl)pyridine8.58 (d, 1H), 7.96 (s, 1H), 7.41-7.32 (m, 4H),diazaspiro[4.5]decan-2-one 7.29-7.23 (m, 1H), 3.75 (s, 2H), 2.41-2.25(m, 2H), 1.98-1.89 (m, 10H), 1.52 (t, 2H). SC_3392cis-8-Dimethylamino-3-(5-fluoro-6- INT-976 4-(5-bromo-3-fluoro-2-SC_3103 1H NMR (600 MHz, CDCl3) δ 8.13 (dd, 1H), 454.3morpholin-4-yl-pyridin-3-yl)-8-phenyl- pyridyl)morpholine 7.76 (d, 1H),7.42 (t, 2H), 7.33 (dd, 3H), 5.84 (s, 1H),1,3-diazaspiro[4.5]decan-2-one 3.84 (t, 4H), 3.52 (s, 2H), 3.37 (t, 4H),2.29-2.12 (m, 4H), 2.08 (s, 6H), 2.01-1.94 (m, 2H), 1.60 (t, 2H).SC_3393 cis-8-(3-Chlorophenyl)-8- INT-1044 5-bromo-4-methyl-2- SC_33191H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 467.2dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H),7.55-7.49 (m, 1H), 7.43-7.37 (m, 1H),(trifluoromethyl)-pyridin-3-yl]-1,3- 7.38-7.29 (m, 3H), 3.61 (s, 2H),2.40-2.24 (m, diazaspiro[4.5]decan-2-one 5H), 1.99-1.90 (m, 8H),1.90-1.76 (m, 2H), 1.60-1.47 (m, 2H). SC_3394cis-8-Dimethylamino-3-[5-(2-oxo-1,3- INT-1049 4-(4,4,5,5-tetramethylSC_3354 1H NMR (600 MHz, DMSO) δ 8.41 (d, 1H), 482.3dihydro-indol-4-yl)-pyridin-2-yl]-8- 1,3,2-dioxaborolan-2- 8.26 (d, 1H),7.92 (dd, 1H), 7.75 (s, 1H), 7.41-7.32 (m,phenyl-1,3-diazaspiro[4.5]decan-2-one yl)indolin-2-one 5H), 7.30-7.23(m, 2H), 7.01 (d, 1H), 6.83 (d, 1H), 3.75 (s, 2H), 3.61 (s, 2H),2.46-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.88 (m, 2H), 1.86-1.82 (m, 2H),1.48 (t, 2H). SC_3395 cis-8-Dimethylamino-8-phenyl-3-[5- INT-9762-bromo-5- SC_3103 1H NMR (600 MHz, DMSO) δ 8.69 (s, 1H), 426.2(trifluoromethyl)-[1,3,4]thiadiazol-2-yl]- (trifluoromethyl)-1,3,4-7.42-7.34 (m, 4H), 7.28 (t, 1H), 3.89 (s, 2H),1,3-diazaspiro[4.5]decan-2-one thiadiazole 2.45-2.31 (m, 2H), 2.07-1.88(m, 8H) 1.88-1.84 (m, 2H), 1.60-1.53 (m, 2H). SC_3397cis-8-Dimethylamino-3-[2-[(2-hydroxy- INT-976 2-{[6-bromo-1-(2- SC_3242(for step 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ (ppm) = 463.3ethyl)-methyl-amino]-1H- trimethylsilanyl- 1), step 2 of 10.62 (bs, 1H),7.48-7.24 (m, 6H), 7.01-6.91 (m, benzoimidazol-5-yl]-8-phenyl-1,3-ethoxymethyl)-1H- SC_3352 (for step 2H,), 6.76 (s, 1H), 4.58 (bs, 1H),3.66 (t, 2H J = 5.62 Hz), diazaspiro[4.5]decan-2-onebenzoimidazol-2-yl]- 2) 3.54-3.50 (m, 4H), 3.09 (s, 3H),methyl-amino}-ethanol 2.37-2.32 (m, 2H), 2.04 (s, 6H), 1.96-1.91 (m,4H), (step 1) 1.52-140 (m, 2H). SC_3398cis-8-Dimethylamino-3-(5-methyl-6- INT-976 4-(5-bromo-2-methyl-2-SC_3103 1H NMR (600 MHz, DMSO) δ 8.23 (s, 1H), 450.3morpholin-4-yl-pyridin-2-yl)-8-phenyl- pyridyl)morpholine 7.83 (s, 1H),7.46-7.33 (m, 5H), 7.30-7.24 (m, 1H), 1,3-diazaspiro[4.5]decan-2-one3.71 (t, 4H), 3.55 (s, 2H), 2.93 (t, 4H), 2.41-2.37 (m, 2H), 1.96 (s,6H), 1.91-1.82 (m, 4H), 1.49-1.44 (m, 2H). SC_3399cis-1-(Cyclopropyl-methyl)-8- SC_3409 bromomethylcyclopropane SC_31051HNMR (DMSO-d6, 400 MHz), δ (ppm) = 501.4dimethylamino-8-(3-fluorophenyl)-3-(5- 8.68-8.68 (d, 1H, J = 2.32 Hz),8.42-8.40 (d, 1H, J = 9.04 Hz), methylsulfonyl-pyridin-2-yl)-1,3-8.18-8.15 (m, 1H), 7.44-7.38 (m, 1H), diazaspiro[4.5]decan-2-one7.20-7.08 (m, 3H), 3.90 (s, 2H), 3.22 (s, 3H), 3.11-3.10 (d, 2H J = 6.68Hz), 2.71-2.68 (d, 2H, J = 13.6 Hz), 2.72-2.21 (m, 2H), 2.00 (s, 6H),1.53-1.44 (m, 4H), 1.02-0.99 (m, 1H), 0.54-0.50 (m, 2H), 0.36-0.35 (m,2H). SC_3400 cis-1-(Cyclopropyl-methyl)-8-(3- SC_3399 SC_3099 1HNMR(DMSO-d6, 400 MHz), δ (ppm) = 487.2 fluorophenyl)-8-methylamino-3-(5-8.72-8.71 (d, 1H, J = 2.28 Hz), 8.42-8.40 (d, 1H, J = 9.04 Hz),methylsulfonyl-pyridin-2-yl)-1,3- 8.18-8.15 (m, 1H), 7.40-7.31 (m, 3H),diazaspiro[4.5]decan-2-one 7.05-7.01 (m, 1H), 3.93 (s, 2H), 3.23 (s,3H), 3.14-3.13 (d, 2H, J = 6.76 Hz), 2.42 (bs, 1H), 2.28-2.23 (m, 2H),1.96-1.88 (m, 5H), 1.79-1.73 (m, 2H), 1.44-1.41 (d, 2H, J = 12.2 Hz),1.06-1.02 (m, 1H), 0.52-0.47 (m, 2H), 0.36-0.33 (m, 2H). SC_3401cis-1-(Cyclobutyl-methyl)-8-(3- SC_3404 bromomethylcyclobutane SC_3105(for step 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm) = 492.1fluorophenyl)-8-methylamino-3-[2- (step 1) 1), SC_3099 (for 9.23 (s,2H), 7.38-7.26 (m, 3H), 7.00 (t, 1H, J = 8.1 Hz),(trifluoromethyl)-pyrimidin-5-yl]-1,3- step 2) 3.86 (s, 2H), 3.30-3.28(d, 2H, J = 7.24 Hz), diazaspiro[4.5]decan-2-one 2.68-2.65 (m, 1H),2.27-2.16 (m, 3H), 2.06-1.78 (m, 13H), 1.46-1.43 (m, 2H). SC_3402cis-1-(Cyclopropyl-methyl)-8- SC_3404 bromomethylcyclopropane SC_31051HNMR (DMSO-d6, 400 MHz), δ (ppm) = 9.21 (s, 492.0dimethylamino-8-(3-fluorophenyl)-3-[2- 2H), 7.45-7.39 (m, 1H), 7.22-7.18(m, 2H), (trifluoromethyl)-pyrimidin-5-yl]-1,3- 7.14-7.09 (m, 1H), 3.84(s, 2H), 3.09 (d, 2H, J = 6.4 Hz), diazaspiro[4.5]decan-2-one 2.70 (d,2H, J = 9.6 Hz), 2.32-2.21 (m, 2H), 2.01 (s, 6H), 1.59-1.46 (m, 4H),1.01-1.00 (m, 1H), 0.54-0.49 (m, 2H), 0.35-0.33 (m, 2H). SC_3403cis-1-(Cyclopropyl-methyl)-8-(3- SC_3402 SC_3099 1HNMR (DMSO-d6, 400MHz), δ (ppm) = 9.25 (s, 478.4 fluorophenyl)-8-methylamino-3-[2- 2H),7.41-7.30 (m, 3H), 7.04 (t, 1H, J = 6.8 Hz),(trifluoromethyl)-pyrimidin-5-yl-]1,3- 3.89 (s, 2H), 3.12 (d, 2H, J =6.8 Hz), 2.41 (bs, 1H), diazaspiro[4.5]decan-2-one 2.27-2.22 (m, 2H),1.93-1.78 (m, 7H), 1.46-1.43 (m, 2H), 1.08-1.03 (m, 1H), 0.51-0.47 (m,2H), 0.33-0.29 (m, 2H). SC_3404 cis-8-Dimethylamino-8-(3- INT-10242-trifluoromethyl-5- SC_3242 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ(ppm) = 437.9 fluorophenyl)-3-[2-(trifluoromethyl)- bromopyrimidine 9.15(s, 2H), 7.75 (s, 1H), 7.44-7.38 (m, 1H), pyrimidin-5-yl-]1,3- 7.21-7.04(m, 3H), 3.73 (s, 2H), 2.38-2.37 (m, 2H), diazaspiro[4.5]decan-2-one2.05 (s, 6H), 2.01-1.85 (m, 4H), 1.57-1.53 (m, 2H). SC_3405cis-1-(Cyclopropyl-methyl)-8- SC_3319 bromomethylcyclopropane SC_31051HNMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm) = 494.3dimethylamino-8-(3-fluorophenyl)-3-[2- 7.39-7.36 (m, 1H), 7.19-7.05 (m,3H), 6.56 (s, methyl-5-(trifluoromethyl)-2H-pyrazol- 1H), 3.78-3.67 (m,5H), 3.10-3.08 (d, 2H, J = 6.12 Hz),3-yl]-1,3-diazaspiro[4.5]decan-2-one 2.64-2.60 (d, 2H, J = 13.32 Hz),2.37-2.26 (m, 2H), 2.09 (s, 6H), 1.61-1.49 (m, 4H), 1.10-1.02 (m, 1H),0.54-0.52 (m, 2H), 0.36-0.33 (m, 2H). SC_3406cis-1-(Cyclopropyl-methyl)-8-(3- SC_3405 SC_3099 1HNMR at 100° C.(DMSO-d6, 400 MHz), δ (ppm) = 480.0 fluorophenyl)-8-methylamino-3-[2-7.39-7.24 (m, 3H), 6.99-6.96 (m, 1H), 6.58 (s,methyl-5-(trifluoromethyl)-2H-pyrazol- 1H), 3.78-3.71 (m, 5H), 3.11-3.10(d, 2H, J = 5.40 Hz), 3-yl]-1,3-diazaspiro[4.5]decan-2-one 2.30-2.23 (m,2H), 1.99-1.92 (m, 5H), 1.79-1.72 (m, 2H), 1.58-1.56 (m, 2H), 1.10-1.00(m, 1H), 0.54-0.52 (m, 2H), 0.36-0.33 (m, 2H). SC_3407cis-8-Methylamino-3-(4-methyl-2- SC_3148 SC_3099 437.3morpholin-4-yl-pyrimidin-5-yl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_3408 cis-3-[5-(Azetidin-1-yl)-3-methyl- INT-1024 5-(azetidin-1-yl)-2-SC_3103 1H NMR (600 MHz, DMSO) δ 7.44-7.36 (m, 438.3pyridin-2-yl]-8-dimethylamino-8-(3- chloro-3-methyl-pyridine 2H),7.20-7.05 (m, 4H), 6.69 (d, 1H), 3.82 (t, 4H),fluorophenyl)-1,3-diazaspiro[4.5]decan- 3.51 (s, 2H), 2.36-2.26 (m, 4H),2.15 (s, 3H), 2-one 1.96 (s, 6H), 1.94-17.6 (m, 4H), 1.49 (t, 2H).SC_3409 cis-8-Dimethylamino-8-(3- INT-1024 2-bromo-5- SC_3103 1H NMR(600 MHz, DMSO) δ 8.67 (dd, 1H), 447.2fluorophenyl)-3-(5-methylsulfonyl- methylsulfonyl-pyridine 8.39 (dd,1H), 8.14 (dd, 1H), 8.04 (s, 1H), 7.42 (td, 1H),pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2- 7.19 (d, 1H), 7.15 (dt, 1H),7.11 (td, 1H), 3.78 (s, one 2H), 3.21 (s, 3H), 2.41-2.37 (m, 2H), 1.97(s, 6H), 1.94-1.75 (m, 4H), 1.54-1.45 (m, 2H). SC_3410cis-3-(6-(azetidin-1-yl)-4-fluoropyridin- INT-976 2-(azetidin-1-yl)-5-SC_3103 3-yl)-8-(dimethylamino)-8-phenyl-1,3- bromo-4-fluoropyridinediazaspiro[4.5]decan-2-one SC_3411cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8- INT-1024 2-(azetidin-1-yl)-5-SC_3103 (dimethylamino)-8-(3-fluorophenyl)-1,3- bromopyridinediazaspiro[4.5]decan-2-one SC_3412 cis-3-(1-(cyclopropanecarbonyl)-3-INT-1024 (5-bromo-3- SC_3103 (trifluoromethyl)-1H-pyrazol-5-yl)-8-(trifluoromethyl)-1H- (dimethylamino)-8-(3-fluorophenyl)-1,3- pyrazol-1-diazaspiro[4.5]decan-2-one yl)(cyclopropyl)methanone SC_3413cis-8-(dimethylamino)-8-(3- INT-1024 2-(5-bromo-3- SC_3242fluorophenyl)-3-(1-(2-hydroxyethyl)-3- (trifluoromethyl)-1H-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3- pyrazol-1-yl)ethanoldiazaspiro[4.5]decan-2-one SC_3414 cis-3-(1-(cyclopropylmethyl)-3-INT-1024 5-bromo-1- SC_3242 480.2 (trifluoromethyl)-1H-pyrazol-5-yl)-8-(cyclopropylmethyl)-3- (dimethylamino)-8-(3-fluorophenyl)-1,3-(trifluoromethyl)-1H- diazaspiro[4.5]decan-2-one pyrazole SC_3415cis-8-(dimethylamino)-8-(3- INT-1024 5-bromo-1- SC_3242fluorophenyl)-3-(1-(methylsulfonyl)-3- (methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3- (trifluoromethyl)-1H-diazaspiro[4.5]decan-2-one pyrazole SC_3416 cis-1-(cyclopropylmethyl)-8-SC_3415 bromomethylcyclopropane SC_3105(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)- 1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3417 cis-2-(5-(8-(dimethylamino)-8-(3-INT-1024 2-(5-bromo-3- SC_3242 fluorophenyl)-2-oxo-1,3-(trifluoromethyl)-1H- diazaspiro[4.5]decan-3-yl)-3- pyrazol-1-yl)-N,N-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N- dimethylacetamidedimethylacetamide SC_3418 cis-2-(5-(1-(cyclopropylmethyl)-8- SC_3417bromomethylcyclopropane SC_3105 (dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan)-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N- dimethylacetamide SC_3419cis-8-(dimethylamino)-3-(1-methyl-1H- INT-976 5-bromo-1-methyl-1H-SC_3103 404.3 pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-pyrrolo[2,3-b]pyridine 1,3-diazaspiro[4.5]decan-2-one SC_3420cis-8-(dimethylamino)-3-(3-fluoro-1H- INT-976 5-bromo-3-fluoro-1-((2-SC_3352 408.2 pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-(trimethylsilyl)ethoxy)methyl)- 1,3-diazaspiro[4.5]decan-2-one1H-pyrrolo[2,3- b]pyridine (step 1) SC_3421cis-8-(dimethylamino)-8-phenyl-3-(1H- INT-976 4-bromo-1-((2- SC_3352390.2 pyrrolo[2,3-c]pyridin-4-yl)-1,3- (trimethylsilyl)ethoxy)methyl)-diazaspiro[4.5]decan-2-one 1H-pyrrolo[2,3- c]pyridine SC_3422cis-8-(dimethylamino)-8-phenyl-3-(2- INT-989 4-(4,4,5,5-tetramethyl-SC_3354 430.2 (pyridazin-4-yl)pyrimidin-5-yl)-1,3- 1,3,2-dioxaborolan-2-diazaspiro[4.5]decan-2-one yl)pyridazine SC_3423cis-8-(dimethylamino)-3-(2-(2-oxo-1,2- INT-989 (2-oxo-1,2- SC_3354 445.2dihydropyridin-4-yl)pyrimidin-5-yl)-8- dihydropyridin-4-phenyl-1,3-diazaspiro[4.5]decan-2-one yl)borortic acid SC_3424cis-8-(dimethylamino)-8-(3- INT-1024 3,5-dibromo-1-methyl- SC_3103 (forstep fluorophenyl)-3-(1-methyl-3-(thiophen- 1H-pyrazole (step 1), 1),SC_3354 (for 2-yl)-1H-pyrazol-5-yl)-1,3- thiophen-2-ylboronic step 2)diazaspiro[4.5]decan-2-one acid (step 2) SC_3425cis-8-(dimethylamino)-8-(3- INT-1024 3,5-dibromo-1-methyl- SC_3103 (forstep fluorophenyl)-3-(1-methyl-3- 1H-pyrazole (step 1), 1), SC_3103 (formorpholino-1H-pyrazol-5-yl)-1,3- morpholine (step 2) step 2)diazaspiro[4.5]decan-2-one SC_3426 cis-8-(dimethylamino)-8-phenyl-1-INT-1068 2-trifluoromethyl-5- SC_3103 502.2 (2,2,2-trifluoroethyl)-3-(2-bromopyrimidine (trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3427 cis-8-(dimethylamino)-8-phenyl-3-(2-INT-1070 2-trifluoromethyl-5- SC_3103(trifluoromethyl)pyrimidin-5-yl)-1- bromopyrimidine(3,3,3-trifluoropropyl)-1,3- diazaspiro[4.5]decan-2-one SC_3428cis-3-(4-methyl-6- SC_3122 SC_3099 (trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3429cis-3-(1-methyl-3-(trifluoromethyl)-1H- SC_3200 SC_3099pyrazol-5-yl)-8-(methylamino)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-oneSC_3430 cis-8-(dimethylamino)-8-(3- INT-1024 3-bromo-4- SC_3103fluorophenyl)-3-(4- (methylsulfonyl)pridine(methylsulfonyl)pyridin-3-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3431cis-8-(dimethylamino)-3-(1-ethyl-3- INT-1024 5-bromo-1-ethyl-3- SC_3242(trifluoromethyl)-1H-pyrazol-5-yl)-8-(3- (trifluoromethyl)-1H-fluorophenyl)-1,3-diazaspiro[4.5]decan- pyrazole 2-one SC_3432cis-3-(1-cyclopropyl-3-(trifluoromethyl)- INT-10245-bromo-1-cyclopropyl- SC_3242 1H-pyrazol-5-yl)-8-(dimethylamino)-8-3-(trifluoromethyl)-1H- (3-fluorophenyl)-1,3- pyrazolediazaspiro[4.5]decan-2-one SC_3433 cis-8-(dimethylamino)-8-(3- INT-10245-bromo-1-(oxetan-3- SC_3242 fluorophenyl)-3-(1-(oxetan-3-ylmethyl)-ylmethyl)-3- 3-(trifluoromethyl)-1H-pyrazol-5-yl)- (trifluoromethyl)-1H-1,3-diazaspiro[4.5]decan-2-one pyrazole SC_3434cis-8-(dimethylamino)-8-(3- INT-1024 5-bromo-1-(2- SC_3242fluorophenyl)-3-(1-(2- (methylsulfonyl)ethyl)-3-(methylsulfonyl)ethyl)-3- (trifluoromethyl)-1H-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3- pyrazolediazaspiro[4.5]decan-2-one SC_3435 cis-8-(dimethylamino)-8-(3- INT-1076methylamine SC_3239 fluorophenyl)-3-(4-methyl-2-(methylamino)pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3436cis-3-(2-cyclopropoxy-4- INT-1076 cyclopropanol SC_3224 440.3methylpyrimidin-5-yl)-8- (dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3437 cis-N-(5-(8-(dimethylamino)-8-(3-INT-1024 N-(5-bromo-4- SC_3103 481.3 fluorophenyl)-2-oxo-1,3-methylpyrimidin-2-yl)- diazaspiro[4.5]decan-3-yl)-4- N-methylpyrimidin-2-yl)-N- methylcyclopropanecarboxamidemethylcyclopropanecarboxamide SC_3438 cis-N-(5-(8-(dimethylamino)-8-(3-INT-1024 N-(5-bromo-4- SC_3103 497.3 fluorophenyl)-2-oxo-1,3-methylpyrimidin-2-yl)- diazaspiro[4.5]decan-3-yl)-4- N-methylpivalamidemethylpyrimidin-2-yl)-N- methylpivalamide SC_3439cis-3-(4-(azetidin-1-yl)-2- INT-1077 azetidine SC_3120 493.2(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3- diazaspiro[4.5]decan-2-oneSC_3440 cis-8-(dimethylamino)-8-(3- INT-1077 oxetan-3-ylmethanol SC_3224524.2 fluorophenyl)-3-(4-(oxetan-3- ylmethoxy)-2-(trifluoromethyl)pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3441cis-3-(2-cyclopropyl-4-(2,2,2- INT-1078 2,2,2-trifluoroethanol SC_3224508.2 trifluoroethoxy)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3- diazaspiro[4.5]decan-2-oneSC_3442 cis-3-(2-cyclopropyl-4-((2- INT-1078 2-(methylamino)ethanolSC_3120 483.3 hydroxyethyl)(methyl)amino)pyrimidin-5-yl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

Chemical Structures of all Examples

Pharmacological Investigations

Functional investigation on the human mu-opioid receptor (hMOP), humankappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), andhuman nociceptin/orphanin FQ peptide receptor (hNOP)

Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay

The hMOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS—HCl(pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin(Sigma-Aldrich Co. St. Louis, Mo.). The final assay volume (250 μl/well)included 1 nM of [N-allyl-2.3-³H]naloxone as ligand (PerkinElmer LifeSciences. Inc. Boston, Mass. USA), and either test compound in dilutionseries or 25 μM unlabelled naloxone for determination of unspecificbinding. The test compound was diluted with 25% DMSO in H₂O to yield afinal 0.5% DMSO concentration, which also served as a respective vehiclecontrol. The assay was started by adding wheat germ agglutinin coatedSPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had beenpreloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc.Boston, Mass. USA). After incubation for 90 minutes at RT andcentrifugation for 20 minutes at 500 rpm the signal rate was measured bymeans of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]naloxone-specificreceptor binding were calculated by nonlinear regression analysis and Kivalues were calculated by using the Cheng-Prusoff equation. (Cheng andPrusoff. 1973).

Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay

The hKOP receptor binding assay is run as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS—HCl(pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of250 μl per well includes 2 nM of [³H]U69.593 as ligand, and either testcompound in dilution series or 100 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hKOP receptor membranes (14.8 μg/250 μl finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 90 minutes at room temperature. After this incubation, themicrotiter plates are sealed with a topseal and centrifuged for 20minutes at 500 rpm. The signal rate is measured after a short delay of 5minutes by means of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac, Turku. Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50%/o displacement of [³H]U69.593-specificreceptor binding are calculated by nonlinear regression analysis and K;values are calculated by using the Cheng-Prusoff equation, (Cheng andPrusoff, 1973).

Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay

The hDOP receptor binding assay is performed as homogeneous SPA-assayusing the assay buffer 50 mM TRIS—HCl, 5 mM MgCl₂ (pH 7.4). The finalassay volume (250 μl/well) includes 1 nM of[Tyrosyl-3,5-³H]2-D-Ala-deltorphin II as ligand, and either testcompound in dilution series or 10 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hDOP receptor membranes (15.2 μg/250 μl finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 120 minutes at room temperature and centrifuged for 20minutes at 500 rpm. The signal rate is measured by means of a 1450Microbeta Trilux β-counter (PerkinElmer Life Sciences/Wallac, Turku,Finland). Half-maximal inhibitory concentration (IC50) values reflecting50% displacement of [Tyrosyl-3.5-³H]2-D-Ala-deltorphin II-specificreceptor binding are calculated by non linear regression analysis and K;values are calculated by using the Cheng-Prusoff equation, (Cheng andPrusoff. 1973).

Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay

The hNOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS—HCl,10 mM MgCl₂. 1 mM EDTA (pH 7.4). The final assay volume (250 μl/well)included 0.5 nM of [leucyl-³H]nociceptin as ligand (PerkinElmer LifeSciences. Inc. Boston, Mass. USA), and either test compound in dilutionseries or 1 μM unlabelled nociceptin for determination of unspecificbinding. The test compound was diluted with 25% DMSO in H₂O to yield afinal 0.5% DMSO concentration, which also served as a respective vehiclecontrol. The assay was started by adding wheat germ agglutinin coatedSPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had beenpreloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc.Boston, Mass. USA). After incubation for 60 minutes at RT andcentrifugation for 20 minutes at 500 rpm the signal rate was measured bymeans of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]nociceptin-specificreceptor binding were calculated by nonlinear regression analysis and Kivalues were calculated by using the Cheng-Prusoff equation. (Cheng andPrusoff. 1973).

hNOP Ki hMOP Ki [nM] or % [nM] or % inhibition at inhibition at Example1 μM 1 μM SC_3001 0.3 120 SC_3002 1.3 250 SC_3003 0.4 350 SC_3004 19.5515 SC_3005 0.7 12 SC_3006 1.1 46 SC_3007 85.8 705 SC_3008 0.6 23SC_3009 1.1 41 SC_3010 2.7 18 SC_3011 4.4 4.4 SC_3012 2.2 120 SC_30131.4 39 SC_3014 0.8 29.5 SC_3015 2.6 32.5 SC_3016 4.2 45 SC_3017 2 30SC_3018 5.2 101.5 SC_3019 10.2 135 SC_3020 10.8 290 SC_3021 1.8 14.5SC_3022 0.4 37.2 SC_3023 7.7 36 SC_3024 1 145 SC_3025 236.7 1530 SC_30264.6 300 SC_3027 5 136 SC_3028 0.6 10.4 SC_3029 1.8 7.3 SC_3030 2.2 59SC_3031 4.1 45.5 SC_3032 11 245 SC_3033 107 38%@10 μM SC_3034 12.2 730SC_3035 6.6 1055 SC_3036 1.4 220 SC_3037 33.5 775 SC_3038 1 76 SC_303913 380 SC_3040 4 335 SC_3041 0.9 79.5 SC_3042 4.1 136.5 SC_3043 70 655SC_3044 230 10920 SC_3045 55.5 520 SC_3046 13.9 63 SC_3047 10.1 2105SC_3048 1 38.5 SC_3049 25 940 SC_3050 85 28 SC_3051 3.6 170 SC_3052 160355 SC_3053 73.5 1200 SC_3054 16.5 29.5 SC_3055 94.5 215 SC_3056 9.849.5 SC_3057 955 245 SC_3058 5 7.8 SC_3059 11.4 320 SC_3060 3 65 SC_30614.7 54.5 SC_3063 0.7 38 SC_3064 119 365 SC_3065 6.2 1990 SC_3066 2.2 96SC_3067 41.5 99.5 SC_3068 5.9 50.5 SC_3069 2.6 49 SC_3070 2.8 12.5SC_3071 8.2 170 SC_3072 5.9 235 SC_3073 1 110 SC_3074 1.6 55 SC_3075 8.1260 SC_3076 0.6 35.3 SC_3077 3.2 325 SC_3078 0.6 77.5 SC_3079 1.6 38.5SC_3080 1.6 90.5 SC_3081 8 1320 SC_3082 39 1110 SC_3083 12 117.3 SC_30841.8 22 SC_3085 1.6 107 SC_3086 1.1 43.5 SC_3087 2.8 99 SC_3088 3.1 770SC_3089 3.3 235 SC_3090 1.3 67 SC_3091 2.3 24 SC_3092 2.2 330 SC_30931.1 47 SC_3094 5.4 45.5 SC_3096 14 250 SC_3097 17 18 SC_3098 2 6 SC_309913 19 SC_3100 1 1 SC_3101 1 3 SC_3102 2 1 SC_3103 7 1 SC_3104 — —SC_3105 2 97 SC_3106 8 165 SC_3107 2 115 SC_3108 5 26 SC_3109 8 19SC_3110 6 20 SC_3111 8 37 SC_3112 36 120 SC_3113 24 26 SC_3114 245 460SC_3115 265 915 SC_3116 6 170 SC_3117 92 1380 SC_3118 80  5% SC_3119 22%10% SC_3120 26 4950 SC_3121 44 30% SC_3122 21 32% SC_3123 82 2260SC_3124 5 1090 SC_3125  3%@10 μM 52%@10 μM SC_3126 0%  0% SC_3127 0%3945 SC_3128 0%  1% SC_3129 6 2180 SC_3130 13 4530 SC_3131 4 3090SC_3132 540  6% SC_3133 19 6515 SC_3134  3%@10 μM 40%@10 μM SC_3135 1% 1% SC_3136 16 5840 SC_3137 5 4235 SC_3138 28  7% SC_3139 59 1690SC_3140 119 2355 SC_3141 34 7855 SC_3142 9 3750 SC_3143 0%  4% SC_31440% 3590 SC_3145 46 1635 SC_3146 18 7675 SC_3147 27 3325 SC_3148 14 4575SC_3149 18 6900 SC_3150 105 16% SC_3151 115 3490 SC_3152 24 4775 SC_315377 2220 SC_3154 17 3575 SC_3155 34 3495 SC_3156 45 6375 SC_3157 35 5690SC_3158 19 2540 SC_3159 13 19% SC_3160 4% 5730 SC_3161 2% 13% SC_3162 51325 SC_3163 28 2095 SC_3164 30 880 SC_3165 4% 17% SC_3166 3% 1640SC_3167 18 3745 SC_3168 11 5 SC_3169 635 3445 SC_3170 7 3610 SC_3171 152010 SC_3172 130  7% SC_3173 10 2525 SC_3174 3% 1265 SC_3175 — — SC_317613 3740 SC_3177 8 4630 SC_3178 6 6700 SC_3179 15 3950 SC_3180 125 2250SC_3181 22 5490 SC_3182 11 2990 SC_3183 165 1415 SC_3184 19 7645 SC_3185335 15% SC_3186 33 2210 SC_3187 87 2240 SC_3188 25 1060 SC_3189 57 3470SC_3190 42 28% SC_3191 27 20% SC_3192 140 4270 SC_3193 100 2480 SC_319428 5120 SC_3195 15 1240 SC_3196 22 1595 SC_3197 44 1680 SC_3198 22 5885SC_3199 19 4020 SC_3200 7 13% SC_3201 115 3885 SC_3202 25 3210 SC_320368 1225 SC_3204 110 14% SC_3205 20 2465 SC_3206 27 2445 SC_3207 39 1505SC_3208 2 3285 SC_3209 — — SC_3210 — — SC_3211 — — SC_3212 9 2005SC_3213 52 18% SC_3214 7 19% SC_3215 0% 14% SC_3216 11 14 SC_3217 232155 SC_3218 83 15% SC_3219 0%  1% SC_3220 10%@10 μM 24%@10 μM SC_322133 1935 SC_3222 6 1910 SC_3223 155 6150 SC_3224 10 1695 SC_3225 13 2520SC_3226 — — SC_3227 16 3785 SC_3228 67 3135 SC_3229 105 3625 SC_3230 1452485 SC_3231 120 2420 SC_3232 15 3475 SC_3233 38 1390 SC_3234 4 1350SC_3235 30 1095 SC_3236 285 18% SC_3237 20 17% SC_3238 4 25% SC_3239 352410 SC_3240 28 17% SC_3241 8 4610 SC_3242 5 675 SC_3243 6 695 SC_324427 4265 SC_3245 67 — SC_3246 11 1025 SC_3247 16 1220 SC_3248 4 41SC_3249 740 855 SC_3250 52 — SC_3251 185 4550 SC_3252 30 — SC_3253 205 —SC_3254 22 240 SC_3255 23 150 SC_3256 12 61 SC_3257 150 240 SC_3258 587125 SC_3259 45 180 SC_3260 570 nd SC_3261 10 63 SC_3262 540 3060SC_3263 66 800 SC_3264 145 130 SC_3265 38 2405 SC_3266 245 1055 SC_3267460 — SC_3268 41 1625 SC_3269 13 5580 SC_3270 305 31 SC_3271 34 245SC_3272 115 4175 SC_3273 — — SC_3274 63 1880 SC_3275 155 124 SC_3276 24130 SC_3277 37 13% SC_3278 12 7035 SC_3279 17 78 SC_3280 6 300 SC_328119 2580 SC_3282 37 3510 SC_3283 12 1030 SC_3284 5 305 SC_3285 15 20%SC_3286 18 5895 SC_3287 119 18% SC_3288 15 115 SC_3289 84 430 SC_3290 166605 SC_3291 350 15% SC_3292 4%  0% SC_3293 3%  0% SC_3294 9 12% SC_329528 2975 SC_3296 10 4530 SC_3297 8 4270 SC_3298 20 17% SC_3299 23 5705SC_3300 22 565 SC_3301 33 2320 SC_3302 31 1025 SC_3303 450 21% SC_33049%  4% SC_3305 10%   0% SC_3306 9 4555 SC_3307 13 5345 SC_3308 2 2575SC_3309 17 6910 SC_3310 7 23% SC_3311 14 27% SC_3312 23 1830 SC_3313 102400 SC_3314 9 4090 SC_3315 14 5325 SC_3316 255 5430 SC_3317 56 6045SC_3318 35 1235 SC_3319 4 15% SC_3320 11 1955 SC_3321 13 5715 SC_3322 121150 SC_3323 27 5530 SC_3324 12%   5% SC_3325 53%@10 μM 20%@10 μMSC_3326 — — SC_3327 17 3360 SC_3328 31 3295 SC_3329 13 4285 SC_3330 141505 SC_3331 2 5265 SC_3332 19 2055 SC_3333 5 1580 SC_3334 17 4005SC_3335 30 2305 SC_3336 240 13% SC_3337 10 1970 SC_3338 36  7% SC_333910 6830 SC_3340 150 5750 SC_3341 15 3460 SC_3342 21 3845 SC_3343 27 16%SC_3344 1 13% SC_3345 4 1800 SC_3346 12 2580 SC_3347 15 4845 SC_3348 254090 SC_3349 8 3980 SC_3350 7 1485 SC_3351 20 2205 SC_3352 37 2160SC_3353 53 15% SC_3354 2 23% SC_3355 52 4785 SC_3356 9 4805 SC_3357 13555 SC_3358 51 7020 SC_3359 66 3520 SC_3360 7 2870 SC_3361 27 5095SC_3362 28 29% SC_3363 33  8% SC_3364 32 4685 SC_3365 2 1655 SC_33661285 14% SC_3367 1220  8% SC_3368 195 11% SC_3369 51 3105 SC_3370 4 14%SC_3371 350  9% SC_3372 125 3535 SC_3373 19 18% SC_3374 55 10% SC_337513 12% SC_3376 37 1720 SC_3377 22 980 SC_3379 11 635 SC_3380 102 5415SC_3381 3 1235 SC_3382 29 13% SC_3383 10 17% SC_3384 6 11% SC_3385 33925 SC_3386 14  0% SC_3387 2 1245 SC_3388 29 185 SC_3389 2 1970 SC_339018 465 SC_3391 53 10% SC_3392 7 4490 SC_3393 88 13% SC_3394 6 735SC_3395 14 4990 SC_3396 44 1730 SC_3397 48 560 SC_3398 9 5640 SC_3399 545% SC_3400 8 635 SC_3401 1 455 SC_3402 7 3630 SC_3403 9 1440 SC_3404 10 5% SC_3405 12 925 SC_3406 24 805 SC_3407 77 13% SC_3408 7 18% SC_340911 25%

Protocol for [³⁵S]GTPγS Functional NOP/MOP/KOP/DOP Assays

Cell membrane preparations of CHO-K1 cells transfected with the humanMOP receptor (Art.-No. RBHOMM) or the human DOP receptor (Art.-No.RBHODM), and HEK293 cells transfected with the human NOP receptor(Art.-No. RBHORLM) or the human KOP receptor (Art.-No. 6110558) areavailable from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1 cellstransfected with the human nociceptin/orphanin FQ peptide (hNOP)receptor (Art.-No. 93-0264C2, DiscoveRx Corporation. Freemont, Calif.)are also used. [³⁵S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham,Mass.).

The [³⁵S]GTPγS assays are carried out essentially as described by Gillenet al (2000). They are run as homogeneous scintillation proximity (SPA)assays in microtiter luminescence plates, where each well contains 1.5mg of WGA-coated SPA-beads. To test the agonistic activity of testcompounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressingcell membranes from CHO-K1 or HEK293 cells, 10 or 5 μg membrane proteinper assay are incubated with 0.4 nM [³S]GTPγS and serial concentrationsof receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4,100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN₃,and 10 μM GDP for 45 min at room temperature. The microtiter plates arethen centrifuged for 10 min at 830 to sediment the SPA beads. Themicrotiter plates are sealed and the bound radioactivity [cpm] isdetermined after a delay of 15 min by means of a 1450 Microbeta Trilux(PerkinElmer. Waltham, Mass.).

The unstimulated basal binding activity (UBS_(obs) [cpm]) is determinedfrom 12 unstimulated incubates and is set as 100% basal binding. Fordetermination of the potency and the efficacy, the arithmetic mean ofthe observed total [³⁵S]GTPγS binding (TB_(obs) [cpm]) of all incubates(duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ,SNC80, DAMGO, or U69,593) are transformed in percent total binding(TB_(obs) [%]) relative to the basal binding activity (i.e. 100%binding). The potency (EC₅₀) of the respective agonist and its maximalachievable total [³⁵S]GTPγS binding (TB_(obs) [%]) above its calculatedbasal binding (UBS_(calc) [%]) are determined from its transformed data(TB_(obs) [%]) by means of nonlinear regression analysis with XLfit foreach individual concentration series. Then the difference between thecalculated unstimulated [³⁵S]GTPγS binding (UBS_(calc) [%]) and themaximal achievable total [³⁵S]GTPγS binding (TB_(calc) [%]) by eachtested agonist is determined (i.e. B1_(calc) [%]). This difference(B1_(calc) [1%]) as a measure of the maximal achievable enhancement of[³⁵S]GTPγS binding by a given agonist is used to calculate the relativeefficacy of test compounds versus the maximal achievable enhancement bya receptor-specific full agonist, e.g. N/OFQ (B1_(calc-N/OFQ) [%]) whichis set as 100% relative efficacy for the hNOP receptor. Likewise, thepercentage efficacies of test compounds at the hDOP, hMOP, or hKOPreceptor are determined versus the calculated maximal enhancement of[³⁵S]GTPγS binding by the full agonists SNC80 (B1_(calc-SNC80) [%]),DAMGO (B1_(calc-DAMGO) [%]) and U69.593 (B1_(calc-U69.593) [%]) whichare set as 100% relative efficacy at each receptor, respectively.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A compound according to general formula (I)

wherein R¹ and R² independently of one another mean —H; —C₁-C₆-alkyl,linear or branched, saturated or unsaturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —OH,—OCH₃, —CN and —CO₂CH₃; a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; whereinsaid 3-12-membered cycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; whereinsaid 3-12-membered heterocycloalkyl moiety is optionally connectedthrough —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; or R¹ and R² together with the nitrogen atom to whichthey are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I; R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; a3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁴means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—; a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 6-14-membered aryl moiety is optionallyconnected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; R⁵ means a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; or a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein “mono- orpolysubstituted” means that one or more hydrogen atoms are replaced by asubstituent independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —R²¹, —C(═O)R²¹, —C(═O)OR²¹,—C(═O)NR²¹R²², —C(═O)NH—(CH₂CH₂—O)₁₋₃₀—CH₃, —O—(CH₂CH₂—O)₁₋₃₀—H,—O—(CH₂CH₂—O)₁₋₃₀—CH₃, ═O, —OR²¹, —OC(═O)R²¹, —OC(═O)OR²¹,—OC(═O)NR²¹R²², —NO₂, —NR²¹R²², —NR²¹—(CH)₁₋₆—C(═O)R²²,—NR²¹—(CH₂)₁₋₆—C(═O)OR²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²¹C(═O)R²²,—NR²¹C(═O)—OR²², —NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —SR²¹, —S(═O)R²¹,—S(═O)₂R²¹, —S(═O)₂OR²¹, and —S(═O)₂NR²¹R²²; wherein R²¹, R²² and R²³independently of one another mean —H; —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —CO₂H,—C(═O)O—C₁-C₆-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₆-alkyl,—C(═O)N(C₁-C₆-alkyl)₂, —O—C₁-C₆-alkyl and —S(═O)₂—C₁-C₆-alkyl; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; wherein said 3-12-membered heterocycloalkyl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl; a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 6-14-membered aryl moiety is optionallyconnected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and—O—C₁-C₆-alkyl; a 5-14-membered heteroaryl moiety, unsubstituted, mono-or polysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl; or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²²,—NR²¹R²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², or—S(═O)₂NR²¹R²² together with the nitrogen atom to which they areattached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—;—(CH₂)₂—S(═O)₂—(CH₂)— or —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H,—C₁-C₆-alkyl, —C(═O)—C₁-C₆-alkyl, or —S(═O)₂—C₁-C₆-alkyl, wherein saidC₁-C₆-alkyl is linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —CO₂H, —C(═O)O—C₁-C₆-alkyl and —C(═O)NH₂; and whereinsaid ring is unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —NH₂, —C₁-C₆-alkyl and—O—C₁-C₆-alkyl; or a physiologically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, and R²⁰ independently of one another mean —H, —F, —OH, or—C₁-C₆-alkyl.
 3. The compound according to claim 1, wherein R¹ means —H;and R² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 4. The compound according toclaim 1, wherein R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 5. The compound according to claim 1, wherein R¹ means—H or —CH₃; and wherein R² means —CH₂-cycloalkyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂-oxetanyl or —CH₂-tetrahydrofuranyl.
 6. Thecompound according to claim 1, wherein R¹ and R² together with thenitrogen atom to which they are attached form a ring and mean—(CH₂)₃₋₆—.
 7. The compound according to claim 1, wherein R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 8. The compound according toclaim 1, wherein R³ means a 6-14-membered aryl moiety, unsubstituted,mono- or polysubstituted.
 9. The compound according to claim 1, whereinR³ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted.
 10. The compound according to claim 1, wherein R⁴ means—H.
 11. The compound according to claim 1, wherein R⁴ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 12. The compound according toclaim 1, wherein R⁴ means a 3-12-membered cycloalkyl moiety, saturatedor unsaturated, unsubstituted, mono- or polysubstituted; wherein the3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 13. The compound according to claim 1, wherein R⁴ meansa 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 14. The compound according to claim 1, wherein R⁴ meansa 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 15. The compound according toclaim 1, wherein R⁴ means a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted; wherein said 5-14-memberedheteroaryl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 16. The compound according to claim 1, wherein R⁵ means-phenyl, unsubstituted, mono- or polysubstituted.
 17. The compoundaccording to claim 1, wherein R⁵ means a monocyclic 5-6-memberedheteroaryl moiety, unsubstituted, mono- or polysubstituted.
 18. Thecompound according to claim 1, wherein R⁵ means a bicyclic 9-10-memberedheteroaryl moiety, unsubstituted, mono- or polysubstituted.
 19. Thecompound according to claim 17, wherein R⁵ means -1,2-benzodioxole,-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl,-imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl,-benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl,-isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl,-benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or-1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted, mono- orpolysubstituted.
 20. The compound according to claim 1, which has astructure according to any of general formulas (II-A) to (VIII-C):

wherein in each case R¹, R², R³, R⁴, and R⁵ are defined as in claim 1,R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; R^(D) means —H, or —F; ora physiologically acceptable salt thereof.
 21. The compound according toclaim 1, wherein R⁵ is selected from the group consisting of:


22. The compound according to claim 1, wherein R¹ means —H or —CH₃; R²means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted;cyclopropyl connected through —CH₂—; or tetrahydropyranyl connectedthrough —CH₂—; R³ means -phenyl, benzyl, -thienyl or -pyridinyl, in eachcase unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —CN, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF3,—OH, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NH₂, —NHCH₃,—N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, SOCH₃ and SO₂CH₃; or R⁴ means —H;—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, —O—C₁-C₄-alkyl, —C(═O)NH—C₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂ or—C(═O)NRR′ wherein R and R′ together with the nitrogen atom to whichthey are attached form a ring and mean —(CH₂)₃₋₅—; 3-6-memberedcycloalkyl, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, whereinsaid 3-6-membered cycloalkyl is connected through —C₁-C₆-alkylene;3-6-membered heterocycloalkyl, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and—O—C₁-C₄-alkyl, wherein said 3-6-membered heterocycloalkyl is connectedthrough —C₁-C₆-alkylene; -phenyl, unsubstituted or monosubstituted with—OCH₃; wherein said -phenyl is connected through —C₁-C₆-alkylene-; or-pyridyl, unsubstituted, mono- or polysubstituted; wherein said -pyridylis connected through —C₁-C₆-alkylene-; R⁵ means -phenyl,-1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl,-thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl,-benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl,-isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl,-benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or-1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of —F; —Cl; —Br; —I; —CN;—C₁-C₄-alkyl; —C₁-C₄-alkyl-OH; —CF₃; —C₁-C₄-alkyl-CF₃;—C₁-C₄-alkyl-C(═O)NH₂; —C₁-C₄-alkyl-C(═O)NHC₁-C₆-alkyl;—C₁-C₄-alkyl-C(═O)N(C₁-C₆-alkyl)₂; —C₁-C₄-alkyl-S(═O)₂—C₁-C₄-alkyl;—C(═O)—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂;—C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —C(═O)NH(C₁-C₄-alkyl-OH);—C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃; —NH₂;—NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH;—NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂;—NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl;—NCH₃C(═O)—C₁-C₄-alkyl; —OH; —O—C₁-C₄-alkyl; —OCF₃; —O—C₁-C₄-alkyl-CO₂H;—O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; —O—C₁-C₄-alkyl-CONH₂; —S—C₁-C₄-alkyl;—S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂;-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,mono- or polysubstituted; wherein said 3-12-membered cycloalkyl isoptionally connected through —CH₂—, —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—,—NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,—C(═O)NCH₃—(CH₂)₁₋₃—; -3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl is optionally connected through —CH₂—,—O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—,—NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; -6-14-memberedaryl, unsubstituted, mono- or polysubstituted; wherein said6-14-membered aryl is optionally connected through —CH₂—, —O—, —NH—,—NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—,—C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or -5-14-membered heteroaryl,unsubstituted, mono- or polysubstituted; wherein said 5-14-memberedheteroaryl is optionally connected through —CH₂—, —O—, —NH—, —NCH₃—,—NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—,—C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; and R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.
 23. The compound according to claim1, which has a structure according to general formula (I′)

wherein R¹ to R⁵, R¹¹ to R²⁰ are defined as in claim 1, or aphysiologically acceptable salt thereof.
 24. The compound according toclaim 1, which has a structure according to general formula (IX) or (X)

wherein R² means —H or —CH₃; R³ means -phenyl or -3-fluorophenyl; R^(C)means —H or —OH; R^(E) means —H, —CH₃, —F, —CF₃, -cyclopropyl,-aziridinyl, —OH; —O—C₁-C₄-alkyl; —OCF₃; —O—C₁-C₄-alkyl-CO₂H;—O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; or —O—C₁-C₄-alkyl-CONH₂; R¹ means—CF₃, -cyclopropyl, —S(═O)₂CH₃, —NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂;—NHC₁-C₄-alkyl-OH; —NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂;—NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl;—NCH₃C(═O)—C₁-C₄-alkyl; -6-14-membered aryl, unsubstituted, mono- orpolysubstituted; or -5-14-membered heteroaryl, unsubstituted, mono- orpolysubstituted; U means=CH— or ═N—; and V means=CH— or ═N—; or aphysiologically acceptable salt thereof
 25. The compound according toclaim 1, which has a structure according to general formula (XI)

wherein R² means —H or —CH₃; R³ means -phenyl or -3-fluorophenyl; R^(H)means —CN; —C₁-C₄-alkyl; —CF₃; —C₁-C₄-alkyl-C(═O)NH₂;—C₁-C₄-alkyl-S(═O)₂—C₁-C₄-alkyl, —C(═O)—C₁-C₄-alkyl; —C(═O)OH;—C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄₋alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —C(═O)NH(C₁-C₄-alkyl-OH);—C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃;-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,mono- or polysubstituted; wherein said 3-12-membered cycloalkyl isoptionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—,—NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,—C(═O)NCH₃—(CH₂)₁₋₃—; or -3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; 6-14-memberedaryl, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl is optionally connected through —CH₂—,—NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—,—NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; R^(G) means —CF₃,—S(═O)₂CH₃; —NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH;—NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂;—NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl;—NCH₃C(═O)—C₁-C₄-alkyl; -3-12-membered cycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered cycloalkyl is optionally connected through —CH₂—, —NH—,—NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—,—C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or -3-12-memberedheterocycloalkyl, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; 6-14-membered aryl, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered heterocycloalkyl isoptionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—,—NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,—C(═O)NCH₃—(CH₂)₁₋₃—; or a physiologically acceptable salt thereof. 26.The compound according to claim 1, which is selected from the groupconsisting ofcis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile;cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylicacid amide;cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrile;cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile;cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylicacid amide;cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile;cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylicacid amide;cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile;cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile;cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide;cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide;cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile;cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonicacid amide;cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylicacid amide;cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6-methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-4-carbonitrile;cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile;cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one;cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile;cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetamide;cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-5-[1-[(1Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;CIS-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile;cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide;cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrile;cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile;cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-pyridine-2-carboxylicacid amide;cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylicacid methyl ester;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzoicacid methyl ester;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyridin-2-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methylsulfonyl-benzonitrile;cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile;cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonicacid amide;cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2-a]pyrazin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-onehydrochloride;cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-onedihydrochloride;cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-methylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;formic acid;cis-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;cis-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;cis-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;cis-4-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;cis-4-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;cis-4-Methoxy-5-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile;cis-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-onecis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(2-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;trans-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile;cis-8-Dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamidecis-8-[(Cyclopropyl-methyl)-methyl-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;trans-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile;cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile;cis-3-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-pyrimidine-2-carboxylicacid amide;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carboxylicacid amide;cis-8-Dimethylamino-3-[2-morpholin-4-yl-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile;cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile;trans-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile;cis-8-Dimethylamino-3-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-aceticacid methyl ester;cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(4-fluoro-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylicacid amide;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-isonicotinonitrile;cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;cis-8-Dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzonitrile;cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzonitrile;cis-8-Dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[2-(Benzylamino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(4-fluorophenyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;trans-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzamide;cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzamide;cis-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;trans-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;trans-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-aceticacid;cis-8-Dimethylamino-8-phenyl-3-(2-piperidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[2-(piperazine-1-carbonyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;trans-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-pyridine-4-carboxylicacid amide; cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[2-(Benzothiazol-6-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(4-phenyl-thiazol-2-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[2-(3,4,5-trifluoro-phenyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-o-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-m-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-p-tolyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoicacid methyl ester;cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoicacid methyl ester;cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoicacid methyl ester;cis-3-(1,3-Benzodioxol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-quinolin-5-yl-1,3-diazaspiro[4.5]decan-2-one;cis-3-(2,3-Dihydro-1H-indol-6-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carboxylicacid methyl ester;cis-8-Dimethylamino-3-(6-methoxy-4-methyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(3-methoxy-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile;cis-8-Dimethylamino-3-(3-methyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(6-methoxy-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one;cis-3-(1,3-Benzodioxol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-aceticacid;cis-8-Dimethylamino-3-[2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;trans-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(2-hydroxy-ethylamino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[2-(Benzyl-methyl-amino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylicacid amide;cis-8-Dimethylamino-3-[2-(1H-indazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-3-([2,1,3]Benzoxadiazol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetamide;cis-8-Dimethylamino-8-phenyl-3-(5-pyridin-4-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-aceticacid methyl ester;cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[2-(3,4-Difluoro-phenyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile;cis-3-(2-Amino-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-cyclopropanecarboxylicacid amide;cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetamide;cis-8-Dimethylamino-8-phenyl-3-(6-piperazin-1-yl-pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile;cis-8-Dimethylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-2-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile;cis-8-Dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carbonitrile;cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carbonitrile;cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(3-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-pyridazin-3-yl-1,3-diazaspiro[4.5]decan-2-one;cis-3-Methoxy-4-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;cis-8-Dimethylamino-3-(2-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;cis-8-Dimethylamino-3-(4-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;cis-8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(morpholin-4-yl-methyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylicacid amide;cis-1-(Cyclopropyl-methyl)-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-methyl-amino]-acetamide;cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]amino]-acetamide;cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-thiophene-2-carboxylicacid amide;cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide;cis-8-Dimethylamino-8-phenyl-3-(5-phenyl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(4-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one(enantiomer 1);cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one(enantiomer 2);cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(4-methyl-6-pyridin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-isoquinolin-4-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-isoquinolin-5-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(enantiomer 1);cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(enantiomer 2);cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[2-(3,3-Difluoro-azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Methylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyloxy)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile;cis-3-[2-(4-Cyclopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[4-methyl-2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carboxylicacid amide;cis-3-[4-(Azetidin-1-yl)-2-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(6-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-acetamide;cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(enantiomer 1);cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(enantiomer 2);cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-3-carboxylicacid amide;cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[4-methyl-6-(3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(4-methyl-6-pyridin-2-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(4-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-2-[8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;cis-8-Dimethylamino-3-[2-(2-methyl-1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methyl-pyrimidin-4-yl]amino]-acetamide;cis-2-[3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridin-4-yl]-acetamide;cis-8-Dimethylamino-3-[4-(methylsulfonyl-methyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[6-(4-methyl-3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(2,4-dimethyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;2,2,2-trifluoro-acetic acid;cis-8-Dimethylamino-3-[6-[(2-hydroxy-ethyl)-methyl-amino]-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]triazol-1-yl]-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-(4-isopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[6-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-nicotinonitrile;cis-8-Dimethylamino-3-(1-methylsulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(2-hydroxy-benzooxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyloxy)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide;2,2,2-trifluoro-acetic acid;cis-8-Dimethylamino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-(1-Acetyl-1H-indol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-nicotinonitrile;cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-nicotinonitrile;cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-pyridine-3-carboxylicacid amide;cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-pyridine-3-carboxylicacid amide;cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-m-tolyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-isonicotinonitrile;cis-8-Dimethylamino-3-[3-fluoro-5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(2-methylamino-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-cyclopropanecarboxylicacid amide;cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylicacid amide;cis-3-[4,6-Bis(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-6-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(2-morpholin-4-yl-quinazolin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-[Methyl-(oxetan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-3-(1-Acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-quinazolin-6-yl-1,3-diazaspiro[4.5]decan-2-one;cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-(2-oxo-1,3-dihydro-indol-4-yl)-isonicotinonitrile;cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylicacid amide;cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,2-trimethyl-propionamide;cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(2-morpholin-4-yl-1H-benzoimidazol-5-yl)-8-phenyl-1,3-8-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(3-fluoro-5-methyl-phenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[6-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(3-hydroxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-3-[6-(Azetidin-1-yl)-5-(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-isonicotinonitrile;cis-3-[3,5-Bis(trifluoromethyl)-pyridin-2-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-onecis-8-Dimethylamino-3-(5-fluoro-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-(3-Chlorophenyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-[1,3,4]thiadiazol-2-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(2-oxo-1,3-dihydro-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-1H-benzoimidazol-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-3-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclobutyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-onecis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one;cis-8-Methylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-[5-(Azetidin-1-yl)-3-methyl-pyridin-2-yl]-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-3-(6-(azetidin-1-yl)-4-fluoropyridin-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;cis-3-(1-(cyclopropanecarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-3-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-2-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide;cis-2-(5-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide;cis-8-(dimethylamino)-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-phenyl-3-(2-(pyridazin-4-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-3-(2-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-morpholino-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one;cis-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(methylsulfonyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;cis-3-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(oxetan-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-(methylsulfonyl)ethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-methyl-2-(methylamino)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-3-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide;cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylpivalamide;cis-3-(4-(azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(oxetan-3-ylmethoxy)-2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;cis-3-(2-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;cis-3-(2-cyclopropyl-4-((2-hydroxyethyl)(methyl)amino)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-oneand the physiologically acceptable salts thereof.
 27. The compoundaccording to claim 1 for use in the treatment of pain.
 28. A medicamentcomprising a compound according to claim 1.